Background
Advances in cancer care depend on evidence derived from clinical trials (CTs) to help practitioners and patients make informed treatment decisions. However, less than 5% of adult patients with cancer participate in CTs [
1] and many trials suffer from insufficient accrual, with earlier phase trial being especially problematic [
2]. Poor accrual and retention have been linked to complex and lengthy consent procedures, which may create difficulties for patients in providing informed consent [
3,
4]. A systematic review evaluating patient understanding of consent for participation in CTs concluded that patients often do not fully understand the potential health risks of novel experimental drugs and have unrealistic expectations of benefit [
5].
Phase I trials, which test the toxicity and safety of a novel treatment in humans, have typically placed research subjects at greater risk of adverse effects with less likelihood of benefit compared to phase II and III trials [
6]. Phase I cancer trials usually involve patients whose disease is advanced or refractory to standard treatment, and who may be more likely to view the CT as their last opportunity to receive treatment [
7]. Such individuals may feel desperate about the severity and progression of their disease, which can undermine their capacity to provide meaningful informed consent [
8,
9].
Recent advances in our understanding of cancer biology and the emergence of precision medicine, with such transformative therapies as immune checkpoint inhibitors and molecularly targeted agents, have altered the cancer CT landscape [
10]. Some phase I cancer trials have become highly targeted and are incorporating elements of later phase CTs. It is not uncommon now to have a combined phase I/II within a single study protocol. These early phase CTs include dose expansion, and allow modification of the trial design based on early evidence of a drug’s efficacy and acceptable toxicity [
11]. These combined phase I/II trials [
12] raise ethical concerns as the distinctions between trial phases becomes blurred, challenging previous understandings of the risks and benefits associated with phase I trials while at the same time offering participants a renewed sense of hope for a cure or delayed disease progression [
13]. Early phase trials thus require special attention to informed consent procedures to ensure research subjects’ understanding of evolving safety and efficacy data, and realistic assessment of risks and benefits [
11].
Given the ethical concerns associated with these modern early-phase CTs, the purpose of this qualitative study was to explore the decision-making process of patients living with cancer who have considered participating in early-phase cancer immunotherapy CTs, including the psychosocial (i.e. the interrelation of social factors, such as age and socio-economic status, with individual thought and behavior) and structural factors (i.e. inequities and unjust power differences in policies and practices) that intersect and influence perceptions of choice and ability to provide informed consent. Consideration of the dynamic influence of psychosocial and structural factors on individual-level decision making is essential to the development of a richer and more comprehensive understanding of CT decision-making processes. This knowledge can enhance ethical CT practices and the development of associated tools, resources, and policies to support patients in making informed decisions about early-phase cancer CTs in this rapidly advancing and complex trial landscape.
Discussion
This study explored patients’ decision making related to early-phase cancer CTs using the lens of relational autonomy. A choice spectrum was uncovered that captures patients’ decision-making experiences, ranging from trial participation being framed as an opportunity to it being perceived as an act of desperation. Our use of the theory of relational autonomy in the construction of our interview guide allowed us to explore and uncover the personal, relational, and larger structural factors that framed this experience. For example, asking questions pertaining the participants motivations and reasons for accepting/declining/withdrawing their participation illustrated how their clinical team influenced participants’ perceived hope and trust that the trial would extend their quality of life and even provide a potential cure, while structural factors, such as trial design and ethical requirements that ensured voluntariness of decisions, enabled the ability of patient participants the option of withdrawing from a trial should they change their mind. A perceived sense of hope and trust that the trial would succeed, and the ability to withdrawal were fundamental attributes that influenced the decision to partake.
Our study findings align with and expand upon previous research. For example, Halpern et al. [
21] illustrate that upwards of 94% of patient-subjects enroll in early-phase CTs with unrealistic therapeutic benefits formed when facing a life-limiting illness that is very difficult to treat. Cox et al. [
22] note that beliefs about therapeutic benefit may be influenced by a myriad of factors including how healthcare professionals working in early-phase CT recruitment communicate with potential participants and the discourse used that could impact patients’ perceptions of choice. For example, the use of the term ‘foolish’ to describe a decision not to enter a CT has significant implications for patients’ decision making, as other studies have also found patients are highly influenced by their physician’s communication [
23]. Additionally, recent studies have also uncovered that some patients perceived they have no other choice but to participate in the trial, perceiving ‘no treatment’ as an untenable option as it means giving up on life [
23,
24]. For those who were ineligible for trials, this led to feelings of despair and uncertainty about their options [
23]. More research is needed that explores patients who are ineligible or who choose not to enroll in clinical trials to offer tailored psychosocial support, especially since one study has found a correlation between moderate to high levels of clinical depression and the decision to decline CT participation [
25].
Applying a relational autonomy lens allowed us to explore potentially influencing factors in more detail by highlighting the overlapping social and structural factors that affected patients’ ability to enact preferred choices and how they were supported in their preference-formation and decision-making process. Many participants shared that they were approached by their physician about taking part in an early-phase trial immediately following the devastating news of a cancer recurrence, progression of disease, or lack of response to standard treatment. This timing and the framing of early-phase cancer immunotherapy trials as the next logical step in treatment may have limited participants’ ability to make a considered decision about trial participation. Patients’ desperation related to the severity of their disease has been identified in previous literature as autonomy-undermining by interfering with persons’ abilities to clearly consider and reflect upon one’s values, interests, and options [
26]. The paradox of obtaining informed consent for early-phase trials in circumstances described by many patients as life versus death, in which they perceive no other options but to choose the trial, has been previously discussed [
27,
28]. While the vulnerability of patients must be acknowledged and addressed in this scenario, the nuanced lens of relational autonomy recognizes that individuals may still have capacity for autonomy, although grounded in important social relationships and influenced by structural factors. Therefore, instead of questioning whether patients have the ability to make their own decisions, a relational autonomy lens encourages the healthcare team and CT personnel to consider ways to support patients so that they are more fully relationally autonomous in the early-phase CT decision making-process. For example, patients’ capacity for autonomy within a relational context would be enhanced by CT personnel taking the time to ensure an individual’s emotional and psychosocial needs are met, that their personal values and beliefs are reflected upon during the decision-making process, and that their understanding and expectations regarding trial outcomes are realistic [
27,
28].
The larger social discourse surrounding cancer and emerging cancer treatments also had an influence on participants and their decision making related to early-phase cancer immunotherapy trials. When faced with a poor prognosis or limited treatment options and the associated fear and desperation, some patients and family members leveraged bellicose metaphors, such as continuing “the fight” against cancer, to provide hope and to support their decision to enter an early-phase trial [
29]. Further, the recent emergence of cancer immunotherapy and precision medicine, and the accompanying discourse regarding the personalized and “natural” immune boosting nature of treatment, has further contributed to patients’ and clinicians’ sense of optimism towards early-phase trials focused on these types of therapies. Acknowledging the powerful influence of these discourses on patients’ decision making and their ability to reflect on their personal values as well as the potential benefits and risks of trial participation may be an important consideration to enhance patients’ relational autonomy in the context of early-phase cancer immunotherapy CTs. There is considerable debate in the scientific and ethics literature about whether phase I trials are likely to provide direct therapeutic benefit in some instances [
6,
30,
31]. We do not weigh in on this debate. Instead, we underscore the need for patients to understand the potential benefits and risks of a particular early-phase trial without hyperbole or unreasonable optimism [
32]. Specifically, immunotherapy is not without potentially life-threatening risk of adverse events, such as neurotoxicities and uncertainty exists regarding the long-term benefits and remission status of patients receiving these therapies [
33]. It behooves physicians when discussing immunotherapy or other targeted cancer CTs to remain committed to providing balanced communication with patients about the purpose of a trial and to clearly explain the associated risks / benefits so as not to engender unrealistic expectation and provide false hope [
23]. Additionally, those who contribute social commentary and public-facing information about novel cancer drugs and CTs such as the media, industry, and trusted cancer centres and organizations, need to be held accountable (perhaps by regulation if not by ethical standards) to present information about modern day CTs fairly, without the use of unjustified superlatives or emotional advertising that obscures a more full appreciation of the risks, benefits, and direct participant costs/resources [
34,
35].
Examining the study findings through a relational autonomy lens highlights the power differential between patients and clinicians, and its potential impact on patients’ perceptions of choice. The trust and sense of indebtedness that many patients feel towards their oncologists, as well as the institution in which they are receiving care, may restrict patients from fully considering their own personal values and preferences when making an early-phase trial decision. In addition, the immutable expertise and scientific knowledge held by oncologists may be prioritized by some patients and motivate them to accept a clinical recommendation to participate in an early-phase trial. The structural location of oncologists as the “gatekeeper” to early-phase CTs may also contribute to a power imbalance that restricts the choices available to patients and families [
36]. In addition, it is important to acknowledge that clinicians and institutions are under pressure and may feel a sense of responsibility to successfully accrue to early-phase trials, not only to contribute to the scientific evidence but to provide patients with the latest advances in cancer treatment [
36].
Applying a relational autonomy lens in this study also uncovered how structural factors, including the design and pre-screening processes associated with an early-phase trial, impacted patients’ decisions and their perceptions of choice. It is important that CT personnel and healthcare professionals recognize how the restrictive eligibility criteria, extensive screening procedures, and conversations about trial participation unintentionally characterize early-phase cancer immunotherapy trials as exclusive and time-limited, which may lead some patients to feel pressure to accept the trial as well as form unrealistic expectations and hope for personal benefit. Successfully making it through the comprehensive early-phase trial screening may also create a situation in which patients feel the trial is tailored to them and that refusing to take part would be nonsensical. Healthcare professionals and CT personnel, thus, need to be aware of how the very structure of immunotherapy or targeted early-phase trials may inadvertently influence patients’ decisions related to trial participation. Being clear in conversations with patients that being an eligible candidate for an early-phase trial does not necessarily equate with receiving direct benefit, including an extension of life, may be an important addition to discussions about trial participation.
In accordance with interpretive description study methodology, we sought to not only interpret what was stated by our study participants, but also to recognize the silences in the data, or what was not alluded to and constituted a marked absence from what may have been expected in the data. Notably, when participants were asked about what was discussed when considering early-phase immunotherapy CT participation, as well as what type of information was important to them, the topic of advance care planning did not emerge at all. Further exploration of how advance care planning and goals of care conversations are managed in this context, and how patients can be supported in considering and evaluating all possible treatment and care options, including palliative care, may be a valuable line of future inquiry. This finding aligns with research that has identified a divergence between patients receiving specialist palliative care and those considering an early-phase trial that is based in misconceptions about palliative care as only applicable near the end of life [
37]. The heavy physical symptoms and psychological burdens that many patients face is highly relevant to the services of specialist palliative care, and it has been argued that earlier education be provided to patients and caregivers to explain the role and opportunity for palliative care throughout the cancer trajectory [
38]. However, when prognosis changes and end of life is near, the social and structural context of cancer care needs to more fully embrace end-of-life care as an acceptable and appropriate option for some individuals, countering the perception of palliative care at this stage of disease as a clinical “failure” [
39]. CT personnel thus need to work closely with a patient’s healthcare team to ensure meaningful discussion about palliative care occur alongside or prior to early-phase trial recruitment procedures. Such discussions will support patients’ re-evaluation of their priorities related to quantity of life versus quality of life, create space for patients and their family members to consider the full spectrum of healthcare alternatives, and enable patients to make a more fully informed and relationally autonomous decision.
Limitations
This was an interpretive descriptive qualitative study undertaken with a cross-sectional design. It is important to acknowledge that the study design restricts our ability to make inferences regarding how the personal, social, and structural factors influence where a participant was located on the choice spectrum with regards to perceiving their decision to participate in an early-phase trial as being an act of desperation or one of opportunity. Future research utilizing other methodologies, such as grounded theory or survey research, may provide further insight into the relationships between these factors and choice perceptions.
In addition, despite our best efforts, we were not able to recruit participants who had withdrawn from, or declined the offer to join, an early-phase CT. Several participants, however, did have experience in declining a CT offer in the past. As such, the study findings must be cautiously applied to all individuals engaging in decisions about early-phase trial participation as the study sample may have captured a select population with regards to attitudes and beliefs towards clinical research and end-of-life care, as well as their overall decision-making experience. Further, the study was conducted at an urban, academic cancer centre with a highly resourced and active early-phase CT program - the experience of individuals living in rural or remote regions and receiving care from community-based oncology programs may be quite different. The study sample, however, was diverse with regards to gender identity, type of cancer, and yearly income.
Lastly, Canada’s commitment to universal health care and the associated stewardship constraints with regards to approving and funding new cancer therapies creates a unique context regarding the role of early-phase CTs in providing individuals access to novel and expensive treatments. Replicating this study in a non-single payer healthcare system, such as the United States, may offer additional insights.
Practice and policy implications
In the context of presenting an early-phase trial to patients, all clinicians and CT personnel need to be meticulous in their language and how they frame and present such trials, including how they discuss screening procedures and the suitability of a person given the trial’s eligibility criteria. Specifically, there must be an explicit description that the trial is research, not treatment, that the benefits are unknown, and the risks are still being understood. In addition, care is needed so that the often-extensive screening procedures associated with early-phase trials (i.e., blood work, biomarker testing, MRI/CT scans) do not create what has been called “hype and hope” [
40], in which patients do not fully appreciate the potential for harm, including having their quality of life suffer for unknown benefit.
From both a practice and policy perspective, it is imperative that the power imbalances that exist between patients and physicians be acknowledged in early-phase CT accrual. There is enormous trust and confidence placed on physicians and their advice; the perception that one’s physician is enthusiastic about a trial and supportive of participation may unintentionally influence patients’ decisions. As such, it is not enough to simply remind patients that their participation in an early-phase trial is voluntary and they can withdraw at any time; instead, a more in-depth conversation needs to occur about their goals of care, where they are in the cancer trajectory, and the social and structural influences that may impact patients’ decisions. For example, unpacking the complex relationship between clinical care and research and how members of the healthcare team may have dual roles as clinicians and researchers may be important to clarify with patients to support them in making a fully informed decision. Guidelines and training for physicians and CT personnel are also required to promote reflection of how power and influence is manifested in early-phase trial discussions and provide them with the skills and insight to have nuanced conversations that support patients’ relational autonomy in the decision-making process.
One way that the power imbalance between patients, physicians, and CT personnel could be addressed is by co-creating opportunities with patients and patient advocacy groups for greater engagement in the planning and design of early-phase CTs. By including patients as equal partners throughout the trial continuum, from conception to translation, not only will power be better distributed, but problematic issues related to patients’ relational autonomy can be identified and addressed. Such an approach has been put forth by both patient advocacy groups (e.g., Colorectal Cancer Canada) as well as national (e.g., Canadian Cancer Trials Group, N2 Canada) and international research alliances (Network Institute of Health and Care in the United Kingdom). These initiatives promote transparency and education regarding the intent, nature, and potential benefits and risks of CTs among patient communities, as well as increase awareness of on-going trials. Such engagement may also lead to more patient-oriented and pragmatic trial designs that allow a more diverse population of individuals to be recruited and retained in trials, and the inclusion of person-centred outcomes that may reflect the needs and values of patients. A national summit to discuss the ethical challenges posed by modern day early-phase trials is urgently needed, especially for trials of breakthrough therapies (i.e., immunotherapy), whose early promising results can create pressure to rapidly implement costly therapies with limited long-term efficacy and safety data into clinical practice.
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