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Advance Care Planning; an Innovative Palliative Care Intervention to Improve Quality of Life in Cancer
Patients - a Multi-Centre Cluster Randomized Clinical Trial

Final Report Summary - ACTION (Advance Care Planning; an Innovative Palliative Care Intervention to Improve Quality of Life in CancerPatients - a Multi-Centre Cluster Randomized Clinical Trial)

Executive Summary:
Introduction

Awareness of preferences regarding medical care should be a central component of the care of patients with advanced cancer. Open communication can facilitate this but can occur in an ad hoc or variable manner. Advance care planning (ACP) is a formalized process of communication between patients, relatives and professional caregivers about patients' values and care preferences. It raises awareness of the need to anticipate possible future deterioration of health. ACP has the potential to improve current and future healthcare decision-making, provide patients with a sense of control, and improve their quality of life.

We studied the effects of the ACP program Respecting Choices on the quality of life of patients with advanced lung or colorectal cancer. In a phase III multicenter cluster randomised controlled trial, 23 hospitals in six countries were randomised: in the intervention sites, patients were offered interviews with a trained facilitator, whereas in the control sites, patients received care as usual. In total, we included 1171 patients. All participating patients completed questionnaires at inclusion, and again after 2.5 and 4.5 months. If a patient died within a year after inclusion, a relative was asked to complete a questionnaire on end-of-life care. Use of medical care was assessed by checking medical files.

The study’s primary endpoint was patients' emotional functioning at 2.5 months post-inclusion. Secondary endpoints were patients quality of life and symptoms, patients' evaluation of decision-making processes, quality of end-of-life care and cost-effectiveness of the intervention. A complementary qualitative study was carried out to explore the lived experience of engagement with the ACTION Respecting Choices ACP program from the perspectives of patients, their Personal Representatives and the facilitators.

Unexpected delays

We requested the European Commission for a budget neutral extension of the project because of several unexpected and exceptional delays that occurred during the project:
Ethics: the overall research ethics approval (including adaptations as requested by national ethics review boards) was in all countries obtained at the end of the first project year, which was according to our planning. However, most clinical sites then turned out to request additional procedures for local approval of the study, which involved a delay of the start of the study of 2 – 6 months.

Preparation of intervention materials: the translation and local adaptation of the intervention materials, including a standardized so-called ‘My Preferences form’ (MPF) and a training programme for facilitators, was more complex than envisaged, because of varying legal regulations and cultural values.

The EU formally agreed with an extension of the project of six months in February 2019. This enabled us to complete patient recruitment and follow-up as planned and to carefully analyse the outcomes of the trials and of the qualitative interview studies. The dates for the deliverables in the last year of the project were adapted accordingly.

Outcomes

The total number of patients that was included was 1117, which is less than the number of 1360 that was needed according to the original research plan. However, our original primary outcome measure was the 4-item emotional functioning subscale (EF4) of the EORTC-QLQ-C30. Whereas the precision and relative validity of the 10-item subscale of the same instrument (EF10), that was also included in our data collection, proved to be better, our final number of recruited patients is sufficient to answer the primary research question with the statistical power as planned.

In the intervention group, 396 patients participated in Respecting Choices ACP conversations (90%). The mean number of facilitated conversations per patient was 1.3 and the mean duration was 93 minutes per conversation. Fidelity analyses showed that facilitators on average delivered 86% of the key elements of the intervention.

The main quantitative outcomes of the trial as well as the cost-effectiveness of the intervention have been described in draft scientific publications that are currently under review or will be submitted to an international medical journal in due course.

Qualitative study

After completing the ACP program, selected patients and their Personal Representatives were invited to take part in a qualitative interview about their experiences. The results of these interviews have been described in draft scientific publications that are currently under review or will be submitted to an international medical journal in due course.

We performed a content analysis of completed My Preferences forms, the advance directive used in the intervention arm of the ACTION trial. In total, 33% of 442 patients who received the ACTION RC ACP intervention completed a My Preferences form. Document completion varied considerably per country: 10.4% (United Kingdom), 20.6% (Denmark), 29.2% (Belgium), 41.7% (the Netherlands), 61.3% (Italy) and 63.9% (Slovenia). Content analysis showed that most patients preferred to be resuscitated; 44% of the patients expressed maximizing comfort as their goal of future care. Most patients preferred 'home' as final place of care.
More details can be found in a published paper.

We are currently performing studies on patients’ perspectives of ACP, patients’ readiness for ACP, the impact of the ACTION RC ACP intervention on the relationship between patients and their personal representatives, and the expression of hope in patients who participated in the ACTION study.

Dissemination

Experiences of performing a large international trial to evaluate a complex intervention in a vulnerable patient group have been widely shared. We published five blog entries at the EAPC website. Preliminary results of the trial and the qualitative add-on study have been presented at five international conferences. We organized an open final conference to present the outcomes of the study that was attended by over 300 delegates from 25 countries.

Until now we have published 6 scientific papers in international peer-reviewed journals. Another 17 papers are currently under review or in preparation.
Twitter has become an important dissemination channel with almost 600 followers.

Project Context and Objectives:
Despite progress in diagnosis and treatment, cancer remains a major life limiting disease, with 12.7 million new cases and 7.6 million cancer deaths worldwide in 2008. Patients with advanced cancer typically suffer from a reduced quality of life and multiple symptoms, such as pain, fatigue, and dyspnoea, due to their cancer diagnosis and/or its treatment .(1) A diagnosis of advanced cancer often has a large impact on patients’ emotional wellbeing, resulting in depression, anxiety and a feeling of loss of control.(2, 3) Medical care for patients with advanced cancer should be aimed at symptom control, psychosocial support, spiritual needs, and practical issues. Patients’ preferences regarding care and their wishes concerning their place of residence should be central. Currently, treatment aimed at prolonging life has been found to often prevail over care aimed at relieving patients’ suffering and enhancing their quality of life, which may not always be in accordance with patients’ needs.(4)

Timely and efficient communication is an important prerequisite for appropriate care that adequately addresses patients’ needs and preferences .(5) However, research findings consistently demonstrate that communication between physicians, patients with advanced cancer, and their relatives is complex. Physicians are often uncertain about their patients’ values and preferences, and relatives may feel stressed, uncertain, and reluctant to relinquish treatment aimed at sustaining life, even if cure is no longer possible.(6)

Advance care planning (ACP) is a formalized process of communication between patients, relatives and professional caregivers. It has been defined as “enabling individuals to define goals and preferences for future medical treatment and care, to discuss these goals and preferences with family and health-care providers, and to record and review these preferences if appropriate”.(7) ACP promotes the documentation of patients’ preferences in their medical file, the communication of these preferences to family and friends, and the periodic review of preferences as circumstances change. It has the potential to empower patients, to foster autonomy, to improve the quality of decision making for patients and relatives, to increase the extent to which care is addressing patients’ needs and preferences, and to reduce patients’ symptom burden.

Studies evaluating the effects of ACP programs are still rather scarce – which is probably due to their challenging nature. We updated recent systematic reviews of randomised controlled trials (RCTs) about ACP (8, 9) and identified five RCTs of complex ACP interventions for advanced cancer patients: one conducted in the UK (n=77) (10), two in Australia (n=120-208),(11, 12) and two in the USA (n=155-223).(13, 14) They found that ACP increased the proportion of patients engaging in conversations about future medical treatment and care, but did not affect satisfaction with healthcare. No effects on place of death and treatment received at the end of life were found, while conflicting results were reported about the completion of ADs and patients’ quality of life. The complex ACP interventions did not increase patients’ level of depression or anxiety, nor were they found to have a detrimental effect on the wellbeing of bereaved caregivers. All RCTs were at high risk of performance, attrition, and other kinds of bias.

One of the most promising ACP programs is the Respecting Choices program. This ACP program was developed in the US and was successfully evaluated in a geriatric setting in Australia, showing that end of life care wishes were much more likely to be known and followed in the intervention group (86%) compared to the control group (30%).(9) In this program, a trained facilitator in collaboration with attending physicians encourages patients to reflect on their goals, values and beliefs, to discuss and document their future choices, and to appoint a surrogate decision maker.

The degree to which elements of ACP are integrated in usual care differs across European countries. In general, patients can express their preferences for care, but their authority to refuse or request treatments varies between countries and open disclosure of prognosis to patients rather than to family is not always made. ACP is a much used and cited concept in the UK, whereas it is not well known by the public or health professionals in Denmark, Slovenia, and Italy. The legal status of ADs differs too. For example ADs are legally valid documents in the United Kingdom, Belgium and the Netherlands, but not in Italy (at the time of the study). Most ACP studies have been performed amongst older nursing home patients with the main aim of establishing patients’ preferences before they lose their competence. We hypothesize that ACP can also be effective in improving the quality of life of competent patients with advanced cancer, because it supports them in timely recognizing and expressing their needs and preferences which will enable strategic and effective planning of care and decision-making. As a result, care will more adequately address patients’ needs and preferences, resulting in improved quality of life and more adequate symptom control, while patients feel more in control and receive less unwanted, futile interventions.

The overall hypothesis that was studied in the ACTION project was: formalized ACP significantly improves quality of life and reduces symptoms of patients with advanced cancer.
The primary study objective was to assess whether ACP improves the quality of life and symptoms of patients with advanced cancer.
Secondary objectives were:
• To assess the effect of an ACP program on the quality of life and symptoms of patients with advanced cancer in different subgroups (gender, age, socioeconomic class, country);
• To assess the effect of ACP on the extent to which care as received is in line with patients’ preferences, on patients’ evaluation of the quality of the decision making process, on the quality of dying of patients with advanced cancer, and on the relatives’ wellbeing;
• To gain insight into how patients, their relatives and professional caregivers experience their involvement in ACP;
• To assess the cost effectiveness of ACP.

References
1. Higginson IJ, Costantini M. Dying with cancer, living well with advanced cancer. Eur J Cancer. 2008 Jul;44(10):1414-24.
2. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007 Mar;18(3):581-92.
3. Brown LF, Kroenke K, Theobald DE, Wu J, Tu W. The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology. 2010 Jul;19(7):734-41.
4. Teno JM, Fisher ES, Hamel MB, Coppola K, Dawson NV. Medical care inconsistent with patients' treatment goals: association with 1-year Medicare resource use and survival. J Am Geriatr Soc. 2002 Mar;50(3):496-500.
5. Borreani C, Brunelli C, Bianchi E, Piva L, Moro C, Miccinesi G. Talking about end-of-life preferences with advanced cancer patients: factors influencing feasibility. J Pain Symptom Manage. 2012 Apr;43(4):739-46.
6. Shalowitz DI, Garrett-Mayer E, Wendler D. The accuracy of surrogate decision makers: a systematic review. Arch Intern Med. 2006 Mar 13;166(5):493-7.
7. Rietjens JAC, Sudore RL, Connolly M, et al. Definition and recommendations for advance care planning: an international consensus supported by the European Association for Palliative Care. Lancet Oncol 2017 Sep;18(9):e543-e551. doi: 10.1016/S1470-2045(17)30582-X.
8. Brinkman-Stoppelenburg A, Rietjens JA, van der Heide A. The effects of advance care planning on end-of-life care: a systematic review. Palliat Med. 2014;28(8):1000-25.
9. Lin C-P, Evans CJ, Koffman J, Armes J, Murtagh FEM, Harding R. The conceptual models and mechanisms of action that underpin advance care planning for cancer patients: A systematic review of randomised controlled trials. Palliative medicine. 2019;33(1):5-23.
10. Jones L, Harrington J, Barlow CA, Tookman A, Drake R, Barnes K, et al. Advance care planning in advanced cancer: can it be achieved? An exploratory randomized patient preference trial of a care planning discussion. Palliative & supportive care. 2011;9(1):3-13.
11. Stein GL, Fineberg IC. Advance care planning in the USA and UK: a comparative analysis of policy, implementation and the social work role. British Journal of Social Work. 2013;43(2):233-48.
12. Johnson SB, Butow PN, Bell ML, Detering K, Clayton JM, Silvester W, et al. A randomised controlled trial of an advance care planning intervention for patients with incurable cancer. British journal of cancer. 2018;119(10):1182.
13. Fischer SM, Kline DM, Min S-J, Okuyama-Sasaki S, Fink RM. Effect of Apoyo con Cariño (Support With Caring) Trial of a Patient Navigator Intervention to Improve Palliative Care Outcomes for Latino Adults With Advanced Cancer: A Randomized Clinical Trial. JAMA oncology. 2018;4(12):1736-41.


Project Results:
1. STUDY DESIGN
We performed a multicenter cluster-randomised clinical trial in 22 hospitals in six European countries (Belgium, Denmark, Italy, the Netherlands, Slovenia and the United Kingdom). Per country pairs of comparable hospitals (academic/non-academic) were randomised to provide either ‘care as usual’ supplemented with ACP or ‘care as usual’. Cluster-randomisation prevents healthcare providers from giving patients in the control group (‘care as usual’) more opportunity to discuss their preferences than usual due to their experience with providing the intervention in the intervention group (‘care as usual’ supplemented with ACP). The nature of the intervention makes blinding, for both healthcare professionals and patients and their relatives, impossible.

2. STUDY POPULATION
We aimed to include 1,360 patients with advanced lung (N=680) or colorectal cancer (N=680). Lung and colorectal cancer patients were selected for this study because both types of cancer have high incidence and mortality rates in Europe and affect both sexes; see Table 1 for in- and exclusion criteria. At inclusion, the average life expectancy of these patients would be about one year; their minimum estimated life expectancy to be eligible for the study was three months.

Table 1

3. THE ACTION RESPECTING CHOICES ADVANCE CARE PLANNING INTERVENTION
In the ACTION trial, we evaluated the ACTION Respecting Choices (RC) Advance Care Planning (ACP) intervention. The ACTION RC ACP intervention is an adapted and integrated version of the RC ® First Steps and Advanced Steps RC facilitated ACP conversation. The RC facilitated ACP conversation is one component of the more comprehensive RC ACP programme that was developed and implemented in La Crosse, Wisconsin, and also includes health care system redesign; the education of the whole health care team; patient and community engagement; and ongoing management with quality improvement. More details can be found at www.respectingchoices.org.

ACTION RC ACP intervention materials were drafted in English and were translated into the languages of the countries participating in the ACTION trial, in close collaboration with the RC programme developers. In this translation process, materials were, where necessary, adapted to local cultural and ethical nuances, whilst not losing the content, structure and integrity of the RC ACP facilitated conversation. In addition, we developed the so-called My Preferences form. The My Preferences form can be used to document the patient’s goals, values, and preferences. Depending on local legal regulations, the My Preferences form can be used as an Advance Directive.

The ACTION RC ACP intervention consists of one or two conversations between the patient and, if he or she wishes, a relative, and a certified facilitator (mostly a nurse). In each country, 4-10 facilitators, in total 39, participated in a two-day RC First and Advanced Steps training programme given by a certified RC teacher. The training programme included role plays, videos demonstrating RC ACP conversations, and one additional day homework assignments. Trained facilitators were certified using competency based criteria. During the ACTION trial, facilitators received regular support and feedback from the RC teacher, based on audio-recorded conversations. Furthermore, facilitators had the opportunity to share their experiences or to discuss difficulties with the RC teachers.

Main elements of the ACTION RC ACP intervention
• ACP conversation guides
The ACTION RC ACP conversations are structured by the use of conversation guides that include scripted questions, information and the integration of general interview (communication) skills. Based on these guides, facilitators support patients and their relatives in exploring the understanding of their illness, in reflecting on their goals, values and beliefs, and in discussing their preferences for future treatment and care. The intervention also supports patients in identifying specific activities and experiences that may contribute to, or detract from, their quality of life and future care planning.
There are three conversation guides that facilitators select for different situations:
The blue guide: for the first conversation with the patient and a personal representative (PR).
The green guide: for the first conversation with the patient, but without a PR.
The yellow guide: for a follow-up conversation with the patient and a PR.
These conversation guides include a variety of topics. To start, patients are supported in identifying a PR, who preferably also attends the follow-up ACTION RC ACP conversation. This enables the PR to become familiar with the patient’s views and wishes and encourages an open dialogue between the patient and the PR. Next, the script continues with the following key topics: what is the patient’s understanding of their disease and possible complications, what did the patient learn from previous experiences with family or friends who became ill and were not able to communicate, what are the patients’ beliefs, what are the patients’ fears and worries, what is the patient hoping for, and what is important for the patient to live well. In addition, the patient’s preferences concerning resuscitation, goals of care, and final place of care are discussed. Finally, patients are informed by the facilitator that they can document their preferences for future medical treatment and care in the My Preferences form. Patients are encouraged to discuss their preferences and questions with their attending physician.
• My Preferences form
The My Preferences form is partly based on the RC Power of Attorney for Healthcare and the Physicians Orders for Life-Sustaining Treatment (POLST) program in the U.S. (www.polst.org). The My Preferences form aligns with topics in the conversation guides and consists of open sections regarding ‘Living well’, ‘Worries and fears’, ‘Beliefs’, and ‘Hopes’, and a structured section in which patients can indicate their preferences regarding Cardio-Pulmonary Resuscitation (CPR), goals of future care, and final place of care as well as other preferences.
• Information leaflets
The facilitators provide leaflets with information regarding ACP and the role of the Personal Representative (PR) to all participants. Where relevant, facilitators also provide leaflets about resuscitation, artificial ventilation and/or artificial feeding. The content of these leaflets was informed by the original RC patient educational materials.
Fidelity
For each facilitator, fidelity assessments were conducted twice. In these assessments, the ACTION RC teachers evaluated to what extent the facilitators adhered to the ACTION RC ACP intervention by assessing to what extent the content of the facilitator’s conversation with patient and, when present, the PR, was in accordance with the ACP Conversation Guide; the facilitator’s general interview (communication) skills; and the overall quality of the ACP conversation.

4. STUDY PROCEDURES
For each participating hospital, baseline background data were collected, such as number of cancer patients attending annually, academic/non-academic setting, number of beds and palliative care services, and a description of common practices regarding ACP and decision-making at the end-of-life. In addition, background reports for each of the six participating countries were created summarizing baseline national and local policies related to the provision of palliative care and ACP.

We translated the Respecting Choices program into the required European languages and adapted its content to the specific legal, clinical, ethical, and cultural contexts of the participating European countries, in an extensive process and in close collaboration with the US developers. To test the intervention and the process for acceptability and efficiency, a feasibility study was conducted with about five patients and potentially their family caregiver in each country. The patients were offered the ACP program and were subsequently interviewed. We also tested the questionnaires during this pilot.

Patients were followed until one year after inclusion. During the inclusion period eligible patients in both intervention and control hospitals, were asked if they were interested in participating in the study by their attending physician. The information provided to patients who were approached in the intervention hospitals and control hospitals was as similar as possible to avoid selection bias with respect to interest in ACP. However, to minimize contamination, patients were informed that the project aimed at investigating the experiences of patients with different approaches towards medical decision-making in advanced stages of cancer, but no details of the Respecting Choices program were revealed to the control group. Patients were given at least 24 hours to consider participation and they were informed that they were free to withdraw from participating in the study without any effect on their care.

Patients in the intervention group were offered the Respecting Choices program in addition to usual care. Depending on the health status of the patient and the content of the conversations, a facilitated interview was expected to last 45-60 minutes on average. We planned to have one or two sessions per patient. The facilitator could assist the patient in documenting preferences, including the assignment of a personal representative. For quality assurance, the interviews were audio- recorded by the facilitator. We developed a standardized checklist to screen a proportion of the interviews for intervention fidelity.

Ethical committee procedures were applied in all countries and institutions involved and approval was provided everywhere. The trial was registered in the International Standard Randomised Controlled Trial Number (ISRCTN63110516). A Data Steering Monitoring Board (DSMB) was established to monitor progress of the study and identify potential risks and other issues.

5. MEASUREMENTS
The following measurements were performed (see Table 2):

Questionnaire study. Patients were asked to complete a written questionnaire about quality of life, symptoms, the decision-making process, patient activation, coping, and satisfaction with care (and the intervention) at baseline (i.e. the moment of inclusion, before the ACP program was delivered in the intervention group), and at 2.5 and 4.5 months after inclusion. If a patient died during follow up (i.e. within one year after inclusion), a relative identified by the patient as next of kin was sent a questionnaire to assess the patient’s quality of end-of-life care and the relative’s own wellbeing.

Medical file study. Data on patients’ survival were collected, as well as preferences as documented and care as received to assess whether patients’ preferred care was congruent with received care. Data on care as received were also used in the cost-effectiveness analysis. These medical files were checked one year post-inclusion with a checklist.
Study of recorded ACP sessions. Data were obtained from audio recorded facilitated interview sessions. Compliance with the intervention was systematically evaluated with a predefined checklist.

Table 2

The web based data collection tool GemsTracker was used to safely store data across hospitals and countries. GemsTracker enables restricted access to selected parts of its content. Legislation in the participating countries regarding research on humans and processing patient data was carefully addressed in all procedures.

6. POWER CALCULATION, SAMPLE SIZE AND FEASIBILITY OF RECRUITMENT
With at least 11 intervention and 11 control hospitals each recruiting 34 lung cancer patients and 34 colorectal cancer patients (of whom 25 in each tumour type group were expected to remain in the study until at least month 2.5) this multicentre cluster-randomised clinical trial was expected to have an overall power of 90% to identify a minimum difference between intervention and control groups of half a standard deviation on the emotional functioning scale of the QLQ-C30 scale, assuming an intra-class correlation (ICC) of 0.1. On country level, these numbers provided a power of 50% to show such a difference (assuming an ICC of 0.05).

The main outcomes were measured at 2.5 months post-inclusion. Although included patients had an expected average life expectancy of at least 3 months, a number of them were assumed to die within 2.5 months after inclusion. Based on Dutch colorectal and lung cancer survival statistics, we conservatively assumed that this would be the case for 15% of included patients. Furthermore, we anticipated that around 10% of included patients would drop out of the study for other reasons, resulting in a total attrition rate of 25%. Based on this attrition rate and an estimated participation rate of 33%, the total number of eligible patients per hospital per cancer type needed to be 101 in a 2-year period, which was considered feasible in the participating hospitals.

7. COST-EFFECTIVENESS STUDY
In order to be able to perform an economic evaluation of the Respecting Choices Action ACP program, every country identified a representative who was knowledgeable in cost prices and/or economic evaluations in healthcare. Four teleconferences were organized with these representatives, the ACTION health economist, and one of ACTION’s coordinators to discuss the task, the findings, the difficulties and solutions. In addition, one-on-one calls were conducted to address country-specific issues.

The cost impact of the intervention was calculated from a healthcare perspective. Information on health care use was obtained from patients’ medical files. Real medical costs were calculated by multiplying the volumes of healthcare use with the corresponding unit prices. Unit prices were calculated for all six countries separately. A ‘Cost Manual: Methodology of cost research and reference prices for economic evaluations in health care ’and a data extraction form were developed, including an overview with all necessary health care use and related cost prices.

8. QUALITATIVE STUDY
A complementary qualitative study was carried out in four of the six countries: the UK, the Netherlands, Italy and Slovenia. The aim of this qualitative study was to qualitatively explore the lived experience of engagement with the Respecting Choices intervention from the perspectives of patients, their Personal Representatives, healthcare providers and Respecting Choices facilitators. After completing the ACP program patients and their Personal Representatives were invited to take part in a qualitative interview about their experiences. In each of the participating countries, the qualitative study was planned to involve between 6-10 cases including a patient and where appropriate a Personal Representative. Further, Respecting Choices facilitators were invited to participate in a focus group meeting to discuss their experiences. All interviews and focus groups were recorded and transcribed verbatim. Data were thematically analysed using a pre-defined coding framework which was developed through an iterative process of discussion and consensus among the research team.

9. ANALYSES
Analyses of the primary and secondary endpoints were performed following the intention-to-treat principle. We fitted a linear hierarchical model with a causal intercept and with hospital as random level, adjusting for country and other relevant variables, taking into account for missing information through a multiple imputation procedure. The same model was fitted both on the primary and on the secondary endpoints. A multilevel modelling approach was used to examine differences in the endpoints between the intervention and control groups, taking account of clustering effects at both hospital and country-level. All statistical tests were two-sided and considered significant if p<0.05.

Missing values
Given the terminal condition of the patients in the ACTION study we expected a relevant percentage of missing values, thus we first performed a literature review on methods to handle missing values. In end of life care studies, a sudden change in the health status, not explainable with the other collected information, could happen, and the missing data could be missing not at random (MNAR). Therefore, we developed a method to handle this type of missing data and we applied it to a provisional sample of the ACTION baseline dataset with 487 records. Up to 39% of follow up data were missing. We performed a sensitivity analysis that explored the departure from the standard missing at random (MAR) assumption which we handled with a multiple imputation by chained equations approach. The sensitivity of the results to depart from the MAR assumption was evaluated on simple indicators, such as means and correlations between variables. Results under MAR and MNAR reflect that the frequency of missing values is indeed related to poor health status. We submitted an article on this topic (Title: Missing not at random in end of life care studies: multiple imputation and sensitivity analysis to data from the ACTION study) to a peer reviewed international journal, which is currently under review.

The primary endpoint
The assessment of the primary outcome of the ACTION trial, emotional functioning (EF), can be improved. In the trial, EF was assessed by a customized 10-item short form (EF10). The EF10 is based on the European Organisation for Research and Treatment of Cancer (EORTC) EF item bank and has the potential for greater precision than the common EORTC Quality of Life Questionnaire Core 30 four-item scale (EF4). We assessed the relative validity (RV) of EF10 compared with EF4. Based on clinical and sociodemographic variables and questionnaire responses of 1028 patients, 53 "known groups" that were expected to differ were formed, for example, females versus males. The EF10 and EF4 were first independently compared within this known group: 45 of the 53 known-groups comparisons were significantly different and were used for calculating the RV. In 41 of 45 (91%) comparisons, the RV was more than 1, meaning that EF10 had a higher RV than EF4. The mean RV of EF10 compared with that of EF4 was 1.41 indicating superior statistical power of EF10 to detect differences in EF. Compared with EF4, EF10 is thus better able to detect changes, which allowed us to reduce the ACTION sample size by 20% to 34% smaller sample size without reducing power. The validity analysis of EF10 versus EF4 has been described in a paper that has been published in Value in Health: Jabbarian LJ, Groenvold M, Petersen MA, Christensen CA, Deliens L, van der Heide A, Kars MC, Miccinesi G, Payne S, Wilcock A, Korfage IJ; ACTION consortium. Assessing Emotional Functioning with Increased Power: Relative Validity of a Customized EORTC Short Form in the International ACTION Trial. Value Health. 2019 Jan;22(1):92-98. doi: 10.1016/j.jval.2018.07.002. Epub 2018 Aug 20.

10. RESULTS
Unexpected delays
We requested the European Commission for a budget neutral extension of the project because of several unexpected and exceptional delays that occurred during the project:
Ethics: the overall research ethics approval (including adaptations as requested by national ethics review boards) was in all countries obtained at the end of the first project year, which was according to our planning. However, most clinical sites then turned out to request additional procedures for local approval of the study, which involved a delay of the start of the study of 2 – 6 months.
Preparation of intervention materials: the translation and local adaptation of the intervention materials, including a standardized so-called ‘My Preferences form’ (MPF) and a training programme for facilitators, was more complex than envisaged, because of varying legal regulations and cultural values.
One important issue was the emphasis on patients making their own anticipatory decisions about future medical treatment the original Respecting Choices (RC) intervention, that was considered less appropriate in our European setting where the emphasis is more on discussing and assessing patients’ preferences to support a process of shared decision making.
It also turned out very sensitive to address issues of medical futility, forgoing treatment, or hastening death in the materials, especially in but not limited to the southern European countries (Italy and Slovenia). We had to work hard to find shared language that was sufficiently clear and acceptable in all countries.
Further, RC materials do not focus on patients with advanced cancer: whereas this patient population is in a specific health condition that requires specific issues to deal with in ACP, the materials needed to include information, questions and considerations regarding e.g. choices concerning oncotherapy.
The MPF is a specific type of advance directive (AD) and whereas the legal status of ADs varies per country, the legal requirements for ADs also vary. We are in fact now analysing the process of the MPF development, that involved 348 documents (emails, minutes, etc.), regular meetings of the ACTION steering committee (including an extra personal meeting with an RC representative at Schiphol airport) and more than 10 versions of the document. The results of this analysis will be presented in a scientific paper that will be submitted for publication.
Representatives of all teams travelled to the US, as planned, to be educated on the intervention and to be trained in delivering the intervention. They subsequently trained facilitators in their own country. Whereas this training had to be as similar as possible in each country, we organized an extra mock training for all teams in Rotterdam, enabling us to fine-tune the ACTION training program, to minimize inter-trainer variability and to maximize fidelity to the intervention.

During the study, the recruitment rate was lower than anticipated. The risk of low recruitment was acknowledged in our original work plan. We fully pursued our contingency plan for this risk by e.g. close monitoring of recruitment, seeking extra hospital departments to recruit patients and by extending the period for recruitment with 14 months.

The EU formally agreed with an extension of the project of six months in February 2019. This enabled us to complete patient recruitment and follow-up as planned and to carefully analyse the outcomes of the trials and of the qualitative interview studies. The dates for the deliverables in the last year of the project were adapted accordingly.

The total number of patients that was included was 1117, which is less than the number of 1360 that was needed according to the original research plan. However, our original primary outcome measure was the 4-item emotional functioning subscale (EF4) of the EORTC-QLQ-C30. Whereas the precision and relative validity of the 10-item subscale of the same instrument (EF10), that was also included in our data collection, proved to be better, our final number of recruited patients is sufficient to answer the primary research question with the statistical power as planned.

Main outcomes of the trial

Between 2015 and 2018, 3,748 patients were considered eligible for the study: 2,748 (73%) of these patients were asked to participate, and 1,135 provided consent to participate. Of these patients, five withdrew their consent. The recruitment rate was 29% in the intervention group (445/1,523) versus 56% in the control group (685/1,225). Thirteen patients did not complete any questionnaires. We thus included data of 1,117 patients in the analyses (442 in intervention and 675 in control group, respectively). The number of patients recruited varied between 3 and 81 across the 23 participating hospitals, with a mean of 37 patients per hospital in the intervention group and 61 in the control group. Patients’ mean age was 66 years. In both groups the majority of patients received systemic anti-cancer treatment at the time of study inclusion. A number of baseline characteristics of the patients differed between the study groups (Table 1). 311 patients in the intervention group (70%) and 498 patients in the control group (74%) completed the first follow-up assessment. These numbers were 265 (60%) and 437 (65%), respectively, for the second follow-up assessment.

Table 3

In the intervention group, 396 patients participated in Respecting Choices ACP conversations (90%). The mean number of facilitated conversations per patient was 1.3 and the mean duration was 93 minutes per conversation. Fidelity analyses showed that facilitators on average delivered 86% of the key elements of the intervention.

The main outcomes of the trial have been described in a draft scientific publication that is currently peer-reviewed by an international medical journal. Details will be provided as soon as this paper has been published.

Cost-effectiveness of the ACTION RC ACP program
We conducted a cost-minimisation study, investigating the difference in healthcare costs between study groups from a healthcare perspective. To analyse the costs of healthcare use during 12 months after inclusion, we took a broad perspective focusing on the costs of hospital care including hospital care (emergency department (ED) visits, hospital stays, ICU care), diagnostic procedures (e.g. blood transfusion or CT scan), medical interventions (e.g. surgery or resuscitation), and medication. To determine whether ACP enhances provision of care that is consistent with patient’s preferences, we investigated whether goals of hospital stays, diagnostic procedures, and medical interventions as described in medical files were in accordance with care preferences, as indicated by participants in their AD(s) (mostly study ADs). In addition, we compared the number of hospital stays, diagnostic interventions, and medical interventions between study groups. Data from both participants’ hospital files were collected in six countries using the same medical file checklist. This checklist was pilot-tested to verify whether relevant care items were accessible in files and to reduce inter-rater differences in interpretations between three researchers who collected these data.

The cost impact of the ACTION RC ACP intervention has been described in a draft scientific publication that will be submitted to an international medical journal in due course. Details will be provided as soon as this paper has been published.

Qualitative study
As a background, we performed a systematic literature review to synthesise and describe research findings on the experiences with advance care planning of patients with a life-threatening or life-limiting illness. The search was performed in MEDLINE, Embase, PsycINFO and CINAHL on 7 November 2016. Of the 3555 articles found, 20 were included. We identified three themes in patients' experiences with advance care planning. 'Ambivalence' refers to patients simultaneously experiencing benefits from advance care planning as well as unpleasant feelings. 'Readiness' for advance care planning is a necessary prerequisite for taking up its benefits but can also be promoted by the process of advance care planning itself. 'Openness' refers to patients' need to feel comfortable in being open about their preferences for future care towards relevant others. We concluded that although participation in advance care planning can be accompanied by unpleasant feelings, many patients reported benefits of advance care planning as well. This suggests a need for advance care planning to be personalised in a form which is both feasible and relevant at moments suitable for the individual patient.

More details can be found in: Zwakman M, Jabbarian LJ, van Delden J, et al. Advance care planning: A systematic review about experiences of patients with a life-threatening or life-limiting illness. Palliat Med. 2018 Sep;32(8):1305-1321. doi: 10.1177/0269216318784474.

To understand how facilitators experience delivering the ACTION RC ACP conversation, seven focus groups involving 28 facilitators from the 6 participating countries have been completed. Focus group discussions have been recorded, transcribed, anonymized, translated into English, and uploaded to NVivo 11 for thematic analysis. Data analysis was a collaborative process between the four countries that participated in the qualitative study, namely Italy, Netherlands, Slovenia and the UK. The facilitators had different professional backgrounds. Although the data showed some cultural differences, six common themes were identified. These themes reflect that most facilitators welcomed the opportunity to participate in the ACTION trial, seeing it as a means of learning new skills in an important area. The script was seen as a prompt to fall back on, but was also experienced as a barrier to having a spontaneous conversation. The facilitators noticed that most patients were positive about having had an ACTION RC ACP conversation and that these conversations prompted patients to become aware of their wishes and to share these. The facilitators observed that it took patients substantial efforts to have these conversations. In response, facilitators took the responsibility to have a conversation patients gained benefit from. Facilitators emphasized the need for training, support and advanced communication skills to be able to work with the script.

More details can be found in a paper that is currently under review.

Writing an Advance Directive (AD) is often seen as a part of ACP. ADs may include specific preferences regarding future care and treatment and information that provide a context for healthcare professionals and relatives in case they have to make decisions for the patient. In a mixed methods study we performed a content analysis and applied descriptive statistics to describe the content of completed My Preferences forms, the AD used in the intervention arm of the ACTION trial. In total, 33% of 442 patients who received the ACTION RC ACP intervention completed a My Preferences form. Document completion varied per country: 10.4% (United Kingdom), 20.6% (Denmark), 29.2% (Belgium), 41.7% (the Netherlands), 61.3% (Italy) and 63.9% (Slovenia). Content analysis showed that 'maintaining normal life' and 'experiencing meaningful relationships' were important for patients to live well. Fears and worries mainly concerned disease progression, pain or becoming dependent. Patients hoped for prolongation of life and to be looked after by healthcare professionals. Most patients preferred to be resuscitated and 44% of the patients expressed maximizing comfort as their goal of future care. Most patients preferred 'home' as final place of care. We concluded that the My Preferences forms provide some insights into patients' perspectives and preferences. However, understanding the reasoning behind preferences requires conversations with patients.

More details can be found in : Zwakman M, van Delden JJM, Caswell G, Deliens L, Ingravallo F, Jabbarian LJ, Johnsen AT, Korfage IJ, Mimić A, Arnfeldt CM, Preston NJ, Kars MC; ACTION consortium. Content analysis of Advance Directives completed by patients with advanced cancer as part of an Advance Care Planning intervention: insights gained from the ACTION trial. Support Care Cancer. 2019 Jul 5. doi: 10.1007/s00520-019-04956-1.

We are currently performing studies on patients’ perspectives of ACP, patients’ readiness for ACP, the impact of the ACTION RC ACP intervention on the relationship between patients and their personal representatives, and the expression of hope in patients who participated in the ACTION study.


Potential Impact:
This ACTION project aimed to improve comfort and quality of life of cancer patients and cancer survivors, and more in general to improved health of European citizens. We evaluated a formalized and promising ACP program (the Respecting Choices program) that may have such an impact through:
• Empowering patients with advanced cancer to efficiently express and discuss their preferences for care, both in the contexts of medical consultations as well as with relatives.
• Improving patient-physician communication.
• Facilitating the delivery of care that is in accordance with the patients’ wishes.

ACP can meaningfully contribute to the development of personalized, integrated care for patients with advanced cancer and may facilitate coordination among health care professionals. In addition, ACP may have the potential to reduce unnecessary use of health care resources.

By studying patients with different types of cancers we increased the generalizability of our findings. The results of the ACTION project have high potential to be transferable to other diseases. Taken together with the fact that our study takes a culturally sensitive perspective, the impact of our project in principle extends to the majority of patients in Europe who are in the last stages of life.

Besides contributing to quality of care and quality-of-life, the project aimed to contribute to sustainable and efficient healthcare systems. One of the novel aspects of this project concerned the cost-effectiveness analysis of ACP. Whereas cost reduction is not the key aim of ACP, it may be a substantial and very favourable effect, which could facilitate the uptake of the program and lower potential financial barriers.

Whereas the main outcomes of the trial have not been published yet, we cannot go into detail about the results in this report. However, many activities to share experiences from the project with a broader audience have been undertaken:
• We delivered six press releases about the project.
• We published nine articles in popular media.
• We regularly published blogs at the EAPC website.
• Several consortium members were interviewed about the project for popular media.
• We delivered 65 oral presentations for a scientific community.
• We delivered 12 poster presentations for a scientific community.
• We delivered 33 oral presentations for a wider audience.
• We organized several (workshops in) scientific conferences.
• We developed and maintained a public website.
• We actively used twitter (@ACPinscience) and had almost 600 followers.
Details about our dissemination activities can be found in the project’s dissemination list.

List of Websites:
www.action-acp.eu/
Agnes van der Heide, a.vanderheide@erasmusmc.nl