Advance care planning in patients with advanced cancer: A 6-country, cluster-randomised clinical trial.

BACKGROUND: Advance care planning (ACP) supports individuals to define, discuss, and record goals and preferences for future medical treatment and care. Despite being internationally recommended, randomised clinical trials of ACP in patients with advanced cancer are scarce. METHODS AND
FINDINGS: To test the implementation of ACP in patients with advanced cancer, we conducted a cluster-randomised trial in 23 hospitals across Belgium, Denmark, Italy, Netherlands, Slovenia, and United Kingdom in 2015-2018. Patients with advanced lung (stage III/IV) or colorectal (stage IV) cancer, WHO performance status 0-3, and at least 3 months life expectancy were eligible. The ACTION Respecting Choices ACP intervention as offered to patients in the intervention arm included scripted ACP conversations between patients, family members, and certified facilitators; standardised leaflets; and standardised advance directives. Control patients received care as usual. Main outcome measures were quality of life (operationalised as European Organisation for Research and Treatment of Cancer [EORTC] emotional functioning) and symptoms. Secondary outcomes were coping, patient satisfaction, shared decision-making, patient involvement in decision-making, inclusion of advance directives (ADs) in hospital files, and use of hospital care. In all, 1,117 patients were included (442 intervention; 675 control), and 809 (72%) completed the 12-week questionnaire. Patients' age ranged from 18 to 91 years, with a mean of 66; 39% were female. The mean number of ACP conversations per patient was 1.3. Fidelity was 86%. Sixteen percent of patients found ACP conversations distressing. Mean change in patients' quality of life did not differ between intervention and control groups (T-score -1.8 versus -0.8, p = 0.59), nor did changes in symptoms, coping, patient satisfaction, and shared decision-making. Specialist palliative care (37% versus 27%, p = 0.002) and AD inclusion in hospital files (10% versus 3%, p < 0.001) were more likely in the intervention group. A key limitation of the study is that recruitment rates were lower in intervention than in control hospitals.
CONCLUSIONS: Our results show that quality of life effects were not different between patients who had ACP conversations and those who received usual care. The increased use of specialist palliative care and AD inclusion in hospital files of intervention patients is meaningful and requires further study. Our findings suggest that alternative approaches to support patient-centred end-of-life care in this population are needed. TRIAL REGISTRATION: ISRCTN registry ISRCTN63110516.

RCT Entities:   Population Interventions Outcomes

Introduction

End-of-life discussions between patients, relatives, and healthcare professionals are associated with less burdensome interventions near death, earlier hospice referrals [1], improved emotional functioning [2,3], and better symptom resolution [3]. Still, timely and adequately providing patients and their families with an opportunity to prepare for the changes wrought by serious progressive illness and to explore patients’ preferences is a challenge [4,5]. Advance care planning (ACP) enables individuals to define goals and preferences for future medical treatment and care, to discuss these goals and preferences with family and healthcare providers, and to record and review these preferences if appropriate [6]. ACP interventions have the potential to prepare patients for decision-making when they are unable to make their own decisions. ACP interventions typically include 1 or more focused, personal conversations between patients and healthcare professionals about patients’ personal values, life goals, and preferences regarding future medical treatment and care. Such conversations have been reported to reduce hospital admissions at the end of life, to increase compliance of provided care with patients’ wishes, and to increase satisfaction with care among older people and nursing home residents [7].

While ACP is a promising approach to improve the quality of life of patients with advanced cancer [7,8], evidence on its effectiveness for this patient group is limited [9]. We updated a 2019 systematic review of randomised controlled trials (RCTs) about ACP for patients with advanced cancer [10] and identified 6 RCTs of complex ACP interventions for advanced cancer patients: 1 conducted in the UK (n = 77) [11], 2 in Australia (n = 120–208) [12,13], and 3 in the US (n = 155–278) [14-16]. In these studies, ACP was found to increase the proportion of patients engaging in conversations about future medical treatment and care, but not to 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 advance directives (ADs) and patients’ quality of life. All RCTs were at high risk of performance bias, attrition bias, or other kinds of bias. We therefore performed a large-scale RCT in 6 European countries to evaluate the effects of a complex ACP intervention on the quality of life, operationalised as emotional functioning, and symptoms of patients with advanced lung or colorectal cancer. Secondary outcomes were coping, patient satisfaction, shared decision-making, patient involvement in decision-making, AD inclusion in hospital files, and use of hospital care.

Methods

Study design

ACTION is a multicentre cluster-randomised controlled trial carried out in 23 hospitals in 6 European countries (Belgium, Denmark, Italy, the Netherlands, Slovenia, and the United Kingdom). We opted for cluster randomisation to prevent contamination. Using a computer-based generator tool, per country and per pair of comparable hospitals (academic or non-academic), hospitals were randomised by the study coordinator to the intervention arm, providing usual care and ACP, or the control arm, providing usual care. Per hospital usually 2 departments participated, e.g., a pulmonology and an oncology department. All patients with advanced lung (stage III or IV) or colorectal cancer (stage IV), WHO performance status 0–3, an estimated life expectancy of at least 3 months, and competence to give consent were eligible (see S1 Text). When a care team considered patients eligible, they were asked to consider participation in ACTION. Patients who wanted to consider participation were contacted by the researcher team and provided with more information about the study. Patients in the intervention hospitals received information about the intervention. Those in control hospitals were informed that ACTION focused on preparing patients for decision-making about care, and that they would receive usual care. Patients were given unrestricted time to consider participation and were informed that they were free to withdraw from participating in the study without any effect on their care. Patients who provided written informed consent were included and followed until 12 months after inclusion. The trial procedures have been described in detail in a protocol paper [17]. The trial was registered in the ISRCTN registry (ISRCTN63110516) as of 10 March 2014. We report the study according to CONSORT reporting guidelines.

The intervention

Respecting Choices (RC) is a comprehensive, structured ACP programme that was developed in La Crosse, Wisconsin, in the US (https://respectingchoices.org/). RC was successfully trialled among older people in Australia [18]. We developed and evaluated the ACTION RC ACP intervention. This was an adapted and integrated version of 2 of the 3 stages of the RC facilitated ACP conversations (First Steps and Advanced Steps). The ACTION RC ACP intervention includes 3 components (see S2 Text): (1) facilitated structured ACP conversations, (2) the My Preferences form, and (3) information leaflets.

Facilitated structured ACP conversations

Healthcare professionals who were certified to deliver the ACTION RC ACP intervention used scripted conversation guides to support patients and their relatives in exploring their understanding of the illness; reflecting on their goals, values, and beliefs; and discussing their preferences for future treatment and care. Depending on the choice of the patient, the intervention involved 1 or 2 conversations, with or without a personal representative being present. Conversations took place in the hospital or at patients’ homes.

My Preferences form

The My Preferences form is a study-specific form where patients can document their preferences (see S3 Text). Depending on local regulations, the My Preferences form may be considered as a formal AD or an informal expression of wishes. It was developed in an iterative process with input from stakeholders, including patient representatives, clinicians, and researchers from all participating countries. It consists of open sections regarding ‘living well’, ‘worries and fears’, ‘beliefs’, and ‘hopes’, and structured sections to indicate preferences regarding cardiopulmonary resuscitation (CPR), goals of future care, and final place of care. Patients were offered the option of completing a My Preferences form, either during or after the ACP conversation. They were advised that they could provide copies to their family and healthcare professionals and could adapt their My Preferences form if needed.

Information leaflets

Information leaflets regarding ACP and the role of the personal representative were provided to all patients who participated in the intervention. Where relevant, patients were also provided with information leaflets about CPR, artificial ventilation, and artificial feeding.

Cross-cultural adaption of intervention and training materials was required to make them appropriate for the countries in this study whilst maintaining the essentials of the content, structure, and integrity of the original intervention. Materials were tested in a feasibility study with 53 patients, 18 relatives, and 29 healthcare professionals and subsequently finalised. Aiming for maximum uniformity in the delivery of the intervention across the 6 countries, all ACTION RC instructors followed the RC First and Advanced Steps training programme together. In each country, an ACTION RC instructor provided facilitators with a 2-day competency-based training programme, in the local language. In total, 39 facilitators, predominantly nurses, were certified.

Per facilitator, fidelity checks were conducted twice, once halfway through the inclusion period and once towards the end of the inclusion period. ACP conversations were audio-recorded, and facilitators’ compliance with the conversation intervention was systematically evaluated by local ACTION RC instructors, using a pilot-tested fidelity checklist that covered the key elements of the conversation guides.

Outcome measures

At baseline and at 11–12 weeks (follow-up assessment 1) and 19–20 weeks (follow-up assessment 2) after inclusion, patients completed a written questionnaire. Quality of life, assessed with 10 items of the European Organisation for Research and Treatment of Cancer (EORTC) emotional functioning item bank [19-21] and symptoms (EORTC QLQ-C15-PAL [22]) were the primary outcomes. Secondary outcomes were coping (COPE, Brief COPE [23-25]), satisfaction with care (items of the EORTC IN-PATSAT [26]), satisfaction with the intervention (9 study-constructed items), shared decision-making (Assessment of Patients’ Experience of Cancer Care [APECC] decision-making self-efficacy scale [27]), and patient involvement in medical decision-making (4 study-constructed items). The availability of completed ADs in the hospital medical file and use of medical care were extracted from medical files in the hospital where patients were recruited. A medical file checklist was developed to allow structured and uniform data collection at 1 year post-inclusion. Due to closure of the data collection, medical files were not checked for patients included after 30 April 2017.

Statistical analysis

We aimed at an overall power of 0.9 (alpha 0.05) to detect a difference between the intervention and control group at the first follow-up assessment of at least 0.5 standard deviation on the 4-item emotional functioning scale (EF4) of the EORTC-QLQ-C30, assuming an intraclass correlation coefficient (ICC) of 0.1 [17]. We expected to include patients in at least 10 intervention and 10 control hospitals (40 departments). We anticipated around 15% of included patients would die before the first follow-up assessment and about 10% would drop out, resulting in an expected attrition rate of 25%. We therefore needed to include 68 participants per hospital, resulting in 1,360 patients [17]. Originally, 22 hospitals were randomised. For logistic reasons, no patients were included in 1 hospital. During the study, 2 additional hospitals were randomised to increase the inclusion rate, resulting in a total number of 23 hospitals.

When during data collection the EORTC emotional function 10-item short form (EF10) appeared to have better precision and relative validity than EF4 [28], we opted for EF10 as our primary outcome measure; the new target number of patients while maintaining the same power was 1,088.

Statistical analyses were by intention-to-treat. Patients lost to follow-up and other missing information were taken into account by performing a multiple imputation (MI) procedure [29]. The MI procedure was implemented using the Multivariate Imputation by Chained Equations (MICE) algorithm with M = 37 imputations [30]. At the end of the MICE procedure we analysed each of the M complete datasets applying standard statistical methods and we combined the results according to Rubin’s rule [29] (see Box A, Table A, and Table B in S4 Text). We compared differences in change scores between the 2 arms and evaluated the association between treatment and each outcome measure using a multilevel regression model with random intercept adjusted for the baseline value of the measure, allowing us to take into account the intraclass correlation occurring between patients attending the same hospital.

Assuming that the RC ACP intervention would not have influenced survival, we planned to perform the analyses on the subset of patients who survived until the first and second follow-up assessments. Moreover, we checked for determinants of emotional functioning apart from the intervention and for an interaction effect of the intervention and country using a multilevel regression model that took into account clustering at the hospital level. The model was adjusted for the baseline level of the measure, country, and individual characteristics (i.e., sex, having children, age, years of education, living with a spouse/partner, living place, religiosity, WHO performance status, current treatment, and cancer stage and type) selected on the basis of the Akaike information criterion for each imputed dataset [31]. Differences were considered significant if p < 0.05 (see Table C in S4 Text).

Ethics

Ethical approval was obtained from research ethics committees in the coordinating centre at Erasmus MC (NL50012.078.14, v02) and in all participating countries. An international data and safety monitoring board monitored the trial and conducted 4 interim analyses during data collection.

Results

Participation and feasibility

Between 21 May 2015 and 6 February 2018, 3,748 patients were considered eligible, 2,748 (73%) were asked to participate, and 1,135 provided consent to participate. Of these, 5 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 included data of 1,117 patients in the analyses (442 in the intervention group and 675 in the control group; see Fig 1). Patients’ mean age was 66 years. In both groups, the majority of patients received systemic anti-cancer treatment at the time of study inclusion (Table 1). During the 1-year follow-up period, 194 patients in the intervention group (44%) and 263 (39%) in the control group died: 30 patients in the intervention group (7%) and 55 patients in the control group (8%) died before follow-up assessment 1, whereas 57 (13%) and 109 (16%) patients, respectively, died before follow-up assessment 2.

Fig 1

Participant flowchart.

Table 1

Sociodemographic and clinical characteristics of ACTION participants.

Characteristic	Intervention group (n = 442)	Control group (n = 675)
Sociodemographic characteristics
Years of education, mean (SD)	13.1 (4.5)	12.9 (4.7)
Missing	56	94
Female sex, n (%)	173 (39)	268 (40)
Living with a spouse/partner, n (%)	303 (69)	497 (74)
Missing	10	17
Having children, n (%)	376 (85)	583 (86)
Missing	8	7
Religiosity, n (%)
Religious	207 (47)	341 (51)
Not religious	174 (39)	228 (34)
Prefers not to specify	51 (12)	93 (14)
Missing	10	13
Considering oneself member of minority group, n (%)	3 (1)	7 (1)
Missing	18	26
Country of residence, n (%)
Belgium	72 (16)	135 (20)
Denmark	68 (15)	68 (10)
Italy	31 (7)	139 (21)
Netherlands	84 (19)	168 (25)
Slovenia	72 (16)	25 (4)
United Kingdom	115 (26)	140 (21)
Clinical characteristic
Diagnosis, n (%)
Lung cancer, stage III or IV	271 (62)	339 (50)
Colorectal cancer, stage IV	171 (38)	336 (50)
Years since diagnosis, mean (SD)	1.2 (1.7)	1.7 (2.4)
Range	0.1–11.5	0.1–33.3
Missing	7	1
Years since diagnosis of current stage, mean (SD)	0.6 (0.9)	1.0 (1.4)
Range	0–6	0–11
Missing	2	3
Receiving systemic treatment1, n (%)	349 (79)	595 (89)
Missing	2	3
WHO performance status2, n (%)
3 In bed/ sitting for more than half of the day	10 (2)	8 (1)
2 Up for more than half of the day	74 (17)	55 (8)
1 No heavy psychical work	243 (55)	343 (51)
0 Fully active	109 (25)	261 (39)
Missing	6	8

1Includes chemotherapy, immunotherapy, and targeted therapy.

Intervention delivery

In the intervention group, 396 patients participated in ACP conversations (90%). Patients had on average 1.3 ACP conversations, which had a mean length of 93 minutes. Fidelity analyses showed that on average 86% of the key elements of the intervention were discussed.

Primary and secondary outcome measures

Since the assumption that the RC ACP intervention did not influence survival was satisfied (p = 0.57 and p = 0.41 at follow-up assessments 1 and 2, respectively), we performed the analyses on the subset of patients who survived until the first and second follow-up assessments (92% and 85% of the sample, respectively). Of patients who survived, 22% and 26% were lost to follow-up at the first and second follow-up assessments, respectively. We found no statistically significant differences between the intervention and control group in change in EORTC emotional functioning score (EF10) at the first (−1.8 versus −0.8, p = 0.59; Table 2) or second (−2.3 versus −0.2, p = 0.10) follow-up assessment. Further analyses showed that there was no interaction effect of intervention and country either (p = 0.41).

Table 2

ICC and changes in outcome scores between follow-up assessment 1 and baseline and follow-up assessment 2 and baseline (with 95% confidence intervals), with p-values from multilevel regression model with random intercept and with hospital as random level adjusting for baseline levels of each endpoint.

Outcome	Follow-up assessment 1 versus baseline				Follow-up assessment 2 versus baseline
	ICC	Intervention group (n = 412)	Control group (n = 620)	p-Value	ICC	Intervention group (n = 385)	Control group (n = 566)	p-Value
Emotional functioning (EORTC EF10)*	0.030	−1.8 (−4.2, 0.7)	−0.8 (−1.5, −0.1)	0.59	0.001	−2.3 (−5.8, 1.2)	−0.2 (−1.4, 0.9)	0.10
Quality of life and symptoms (EORTC QLQ-C15-PAL)^
Overall quality of life	0.053	−5.7 (−14.2, 2.9)	−2.0 (−4.0, 0.1)	0.22	0.026	−5.4 (−13.8, 2.9)	−1.4 (−3.6, 0.8)	0.23
Emotional functioning	0.030	−3.6 (−8.2, 1.1)	−1.7 (−3.4, 0.1)	0.90	0.003	−5.0 (−12.5, 2.5)	−3.3 (−7.5, 1.0)	0.95
Physical functioning	0.049	−6.5 (−16.3, 3.3)	−5.6 (−14.0, 2.9)	0.56	0.022	−8.8 (−23.1, 5.4)	−5.5 (−13.8, 2.8)	0.06
Pain	0.015	6.0 (−9.7, 21.6)	4.3 (−7.4, 16.0)	0.45	0.019	8.4 (−12.4, 29.1)	3.9 (−6.9, 14.7)	0.05
Dyspnoea	0.045	5.4 (−9.7, 20.5)	4.5 (−7.9, 16.8)	0.53	0.030	5.8 (−10.5, 22.1)	5.5 (−9.2, 20.2)	0.63
Insomnia	0.031	−0.9 (−4.5, 2.7)	1.0 (−4.5, 6.5)	0.29	0.034	2.6 (−7.5, 12.7)	−0.3 (−4.2, 3.6)	0.42
Appetite loss	0.036	5.2 (−9.7, 20.2)	3.8 (−7.3, 14.9)	0.69	0.023	8.6 (−13.4, 30.6)	5.9 (−9.8, 21.5)	0.38
Constipation	0.024	1.2 (−5.8, 8.2)	2.2 (−5.6, 10.0)	0.69	0.023	1.0 (−5.8, 7.7)	3.5 (−7.0, 14.1)	0.75
Fatigue	0.026	5.3 (−9.1, 19.7)	2.8 (−6.0, 11.5)	0.36	0.025	7.0 (−11.1, 25.1)	3.5 (−6.8, 13.8)	0.15
Nausea/vomiting	0.010	2.7 (−6.0, 11.4)	2.0 (−4.8, 8.9)	0.88	0.010	3.2 (−6.6, 13.0)	3.4 (−6.1, 12.8)	0.99
Shared decision-making (APECC decision-making self-efficacy scale)^	0.098	−3.3 (−7.3, 0.7)	−1.8 (−3.6, 0)	0.77	0.095	−2.5 (−5.0, 0.1)	−3.2 (−6.9, 0.6)	0.24
Patient involvement in medical decision-making^	0.022	1.7 (−4.5, 7.8)	−1.9 (−3.9, 0.2)	0.33	0.026	2.5 (−5.4, 10.3)	−1.9 (−4.2, 0.4)	0.33
Coping (COPE)^
Denial	0.040	0.2 (−4.4, 4.8)	2.6 (−5.6, 10.7)	0.63	0.070	1.0 (−5.1, 7.0)	2.8 (−6.0, 11.5)	0.75
Acceptance	0.067	−3.7 (−8.2, 0.9)	−3.0 (−6.6, 0.6)	0.58	0.040	−5.7 (−14.1, 2.7)	−3.2 (−7.2, 0.8)	0.99
Problem focused	0.079	−4.8 (−11.0, 1.5)	−3.7 (−8.6, 1.2)	0.76	0.073	−5.0 (−11.5, 1.6)	−3.6 (−8.0, 0.8)	0.78
Satisfaction with care (EORTC IN-PATSAT)^
Information provision by doctors	0.055	−3.3 (−6.8, 0.2)	−3.3 (−7.4, 0.9)	0.59	0.060	−2.6 (−5.1, −0.1)	−5.4 (−13.7, 2.9)	0.57
Information provision by nurses	0.046	−3.3 (−7.1, 0.5)	−3.9 (−9.0, 1.3)	0.56	0.047	−3.3 (−7.1, 0.6)	−5.6 (−14.1, 3.0)	0.23
General rating of received care	0.067	−3.9 (−9.1, 1.3)	−4.5 (−11.2, 2.1)	0.54	0.054	−5.0 (−12.5, 2.4)	−6.3 (−16.4, 3.8)	0.45

The analyses are performed on imputed data (M = 37 imputations) on patients who survived to follow-up assessment 1 (N = 1,032; 85 deaths before follow-up assessment 1) for analyses on follow-up assessment 1 and on patients who survived to follow-up assessment 2 (N = 951; 166 deaths before follow-up assessment 2) for analyses on follow-up assessment 2.

*The score is transformed to a T-score metric with a general population mean of 50 (standard deviation 10).

^Possible score ranges from 0 to 100.

APECC, Assessment of Patients’ Experience of Cancer Care; EF10, emotional function 10-item short form; EORTC, European Organisation for Research and Treatment of Cancer; ICC, intraclass correlation coefficient.

Change scores did not differ between arms for the EORTC QLQ-C15-PAL scales, coping, satisfaction with care, patient involvement in decision-making, or shared decision-making (Table 2). In the intervention group, 147 of 396 (37%) patients who had ACP conversations provided their facilitators with a copy of their completed My Preferences form. It is not known how many others completed the My Preferences form or another document indicating their preferences.

We analysed the medical files of 365 patients (83%) in the intervention group and of 583 control patients (86%). At 12 months post-inclusion, 37 medical files (10%) of patients in the intervention group contained ADs versus 15 in the control group (3%; p < 0.001). Indications that personal representatives were appointed were more often found in medical files of patients in the intervention group (33 versus 7 times, p < 0.001). During the 12 months of follow-up, 61% of patients in the intervention group and 56% of patients in the control group were hospitalised (p = 0.14). Their average number of inpatient hospital days was 15 and 14, respectively (p = 0.5; Table 3). In the intervention group, relatively more patients had used specialist palliative care services (n = 134 [37%] versus n = 160 [27%]; p = 0.002; Table 3).

Table 3

The documentation of preferences in medical files and the use of hospital care.

Outcome	Intervention group (n = 442)	Control group (n = 675)	p-Value
AD in medical file
Completed AD in medical file, n (%)	37 (10)	15 (3)	<0.001*
Missing	77	92
Type of AD, n (%)
My Preferences form	31	Not applicable
Other AD	8 (2)	15 (3)	0.71*
Appointment of personal representative, n (%)	33 (28 MPF, 4 other, 1 both) (94)	7 (47)	<0.001*
Missing	2	0
Hospital care
Any hospitalisation, n (%)	222 (61)	328 (56)	0.17*
Missing	77	92
If any hospitalisation, number of days, mean (SD, range)	15 (13, 0–63)	14 (13, 0–75)	0.53^
Use of specialist palliative care, n (%)	134 (37)	160 (27)	0.002*
Missing	78	92

*Chi-squared test on observed values.

^Unpaired t test.

AD, advance directive; MPF, My Preferences form.

Sixty-seven percent of patients considered the ACP conversations ‘quite or very helpful’, and 16% considered them ‘quite or very stressful’ (Table 4). Three serious adverse events (SAEs) related to the intervention were reported: 1 patient was distressed after reading the study materials and 2 after an ACP conversation. These SAEs were resolved.

Table 4

ACP process and its evaluation by patients.

ACP process outcome	Patients in intervention group (n = 442)
Patients who had ACP conversations; n (%)	396 (90)
Number of conversations per patient; mean (range)	1.3 (1–3)
Length of conversations in minutes; mean (SD, range)	93 (43; 4–303)
One or more relatives attended ACP conversation; n (%)
First conversation (n = 394)	262 (67)
Second conversation (n = 116)	95 (82)
Third conversation (n = 2)	2 (100)
Questions about the ACP process (n = 303)*
Evaluation of number of conversations; n (%)
Too few	30 (10)
Just right	265 (89)
Too many	3 (1)
Timing of ACP conversations; n (%)
Too early	48 (16)
Just right	228 (76)
Too late	25 (8)
ACP conversations considered to be helpful; n (%)
Not at all	18 (6)
A little	82 (27)
Quite a bit	119 (39)
Very much	84 (28)
ACP conversations considered distressing; n (%)
Not at all	171 (56)
A little	86 (28)
Quite a bit	32 (11)
Very much	14 (5)

*Questions about the ACP process were included in follow-up questionnaires 1 and 2. If a participant answered the questions in both questionnaires, only the answers to follow-up questionnaire 2 were included.

ACP, advance care planning.

Discussion

We performed a large randomised controlled trial evaluating the effects of ACP. In 23 hospitals across 6 countries, we included 1,117 patients with advanced lung or colorectal cancer. Patients in the intervention group had ACP conversations with certified facilitators. We did not find any difference in effect on patients’ quality of life, symptoms, coping, satisfaction with care, or shared decision-making at 11–12 weeks post-inclusion, nor did we find an effect on hospital admissions during 1 year of follow-up compared to the control group. Patients in the intervention group used specialised palliative care more often. Hospital files of patients in the intervention group contained ADs, and indications of appointed personal representatives as part of the ADs, more often than those of patients in the control group.

In both the intervention and the control arm, scores for shared decision-making, information as provided by doctors or nurses, and the rating of care as received declined from baseline. This unexpected finding could potentially be explained by increased awareness through study participation of the complexity of decision-making and information provision.

Strengths and limitations

An important feature of our trial is its pragmatic nature, focusing on actual practice in countries with different healthcare systems and end-of-life care cultures, and varying degrees of familiarity with ACP, which increases the external validity and generalisability of our findings. An additional strength is the high-quality research design in which we evaluated a uniform, multi-component ACP intervention that included structured, facilitated conversations, a uniform cross-cultural training programme, and fidelity evaluations. In addition, we developed the My Preferences form, aiming to enable participants to document their preferences in a format that was socially, culturally, legally, and ethically acceptable in all 6 participating countries. In a content analysis of 123 My Preferences forms, it was found that 43.9% of patients opted for comfort-focused care only; 75 preferred home as the final place of care, 20 preferred hospice, and 10 preferred hospital [32]. We included 1,117 patients, which is above the target number of 1,088 [28]. The ICC as observed for the primary outcome (EF10) turned out to be smaller than was assumed at the design stage, thus enhancing the trial power [33].

The study also has limitations. First, fewer eligible patients in the intervention group were asked to participate than in the control group (66% versus 84%), suggesting some level of gatekeeping [34]. In addition, recruitment rates were higher in control than in intervention hospitals. These factors may have resulted in unmeasured baseline differences between the study groups, which may also explain the fact that mortality rates were higher in the intervention than in the control arm. A systematic review of recruitment issues in palliative care randomised controlled trials identified a number of barriers to recruitment that also appeared to be issues in this trial [34]. These include patients not being interested in the intervention, the burden of illness, and gatekeeping by healthcare professionals. We also know from the general literature that healthcare professionals struggle to introduce ACP and discuss end-of-life care issues. Further research is required to explore the complexity of recruitment in palliative care trials [35].

Second, information materials for the control groups also referred in some detail to the intervention. Although we support this from an ethical viewpoint, the information may have alerted patients in the control group to engage in decision-making processes and so may have reduced the contrast between the groups. Third, analyses were carried out on survivors only, whereas survivor average causal effect modelling or partly conditional inference could be a more sophisticated approach to address truncation by death [36,37]. However, in our data no significant differences were found in the proportion of patients who died between the intervention and control arm, and these proportions were small, especially at follow-up assessment 1. Fourth, the number of ACP conversations was limited to an average of 1.3 per patient. This may have affected the impact of the ACP programme. Finally, attrition of patients, although expected in this population, was rather high. Despite these limitations, the trial provides rigorous evidence of the effect of an internationally recognised programme. The results suggest both the challenges of timely discussion of preferences—and aligning the care of patients with advanced cancer accordingly—and the relevance of conducting randomised evaluation of interventions such as ACP programmes.

Several studies outside Europe have reported positive effects of comparable ACP programmes on various outcomes. For instance, the RC programme was found to increase satisfaction with care among older hospitalised patients in Australia [18]. RC facilitation improved the ACP knowledge and decreased the willingness to undergo life-sustaining treatments of ambulatory geriatric patients in the US [38]. However, in a recent study into the effects of facilitated ACP among frail older people in a Dutch population, no effects on quality of life were found [39].

The lack of comprehensive evidence of a positive impact of the complex ACP intervention evaluated in this study may be explained by (1) 1 or more of the characteristics of the intervention, (2) choice and timing of outcome measures, or (3) patients’ preferences regarding ACP and ADs.

The first explanation relates to potential inadequacies of the intervention. We could not ensure that ACP documents were routinely completed, included in the medical notes, and acted upon by physicians. Also, the intervention was delivered in a research context, which required standardisation. As a result, the programme was not integrated with routine services, nor adapted to local circumstances and needs, which may have reduced its effect. For future research we would recommend exploring all options for broader involvement at the institutional level. Further, although patients were offered 2 conversations, the number of ACP conversations was limited to an average of 1.3 per patient. This may have affected the impact of the ACP programme.

The second potential explanation is that the choice and timing of outcome measurements may have been suboptimal. Our primary outcome measure was quality of life, operationalised by the EORTC emotional functioning items, at 11–12 weeks of follow-up. In 2017, a large international Delphi panel agreed that quality of life is not the most appropriate outcome of ACP [6]. Goal-concordant care might have been a better primary outcome, but is very difficult to measure because a validated measure to assess goal-concordant care is lacking [40]. Other studies have discussed the complexity of determining the right outcome measure of ACP studies as well [16,39,41]. Effects of ACP could also predominantly occur in the relational domain: patients and relatives may indeed have been supported to discuss and exchange views about values, goals, and preferences, but this outcome was not explicitly assessed in our trial. The qualitative data as collected in the ACTION trial may shed some light on these potential effects. Although we checked medical files up until death for some patients, the timing of our outcome measurement may have been suboptimal: effects may occur at a later stage for at least some patients, at a time when their situation deteriorates and actual decisions have to be made.

The third potential explanation is that patients may prefer not to fully engage in ACP or make ADs. At the start of the study, the concept of ACP was almost unknown in Denmark [42], Italy, and Slovenia, and ADs had no legal status in Italy [17,43]. The lower recruitment rate in the intervention arm suggests that engaging in ACP in a study context was not attractive for all patients, the majority of whom received anti-cancer treatment. This is supported by 16% of participants reporting the ACP conversations to be distressing. Further, patients may feel reluctant to document specific preferences as these preferences may change [44], or patients may not consider documentation meaningful, either because they find it hard to envisage the future or because they trust their family or physician to decide what is best.

We conclude that in our large trial in European patients with advanced cancer, we did not find effects of the ACTION RC ACP intervention on quality of life, coping, patient satisfaction, or shared decision-making. Potential explanations relate to characteristics of the intervention, patients’ preferences regarding ACP, and the choice of outcome measures. The increase in use of specialist palliative care and of inclusion of ADs in hospital files among patients who received the intervention is meaningful and requires further study. Our findings suggest that additional approaches to support patient-centred end-of-life care and to improve quality of life in this population are needed.

(DOCX)

Click here for additional data file.

Inclusion and exclusion criteria of the ACTION study.

(DOCX)

Click here for additional data file.

Description of the ACTION RC ACP intervention.

(DOCX)

Click here for additional data file.

The My Preferences form.

(DOCX)

Click here for additional data file.

Supporting box and tables.

Box: Handling of missing data. Table A: Number and proportion of missing values for sociodemographic and clinical variables, and for the questionnaire items used to build the scores. Table B: Distribution of loss to follow-up at follow-up assessments 1 and 2 by sociodemographic and clinical variables among surviving patients, with p-value from chi-squared test. Table C: Treatment effect on emotional functioning.

(DOCX)

Click here for additional data file.

1 Mar 2020

Dear Dr Korfage,

Thank you for submitting your manuscript entitled "Advance care planning in patients with advanced cancer; a six country, cluster-randomized clinical trial" for consideration by PLOS Medicine.

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4 Jun 2020

Dear Dr. Korfage,

Thank you very much for submitting your manuscript "Advance care planning in patients with advanced cancer; a six country, cluster-randomized clinical trial" (PMEDICINE-D-20-00632R1) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

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Requests from the editors:

*Please structure your abstract using the PLOS Medicine headings (Background, Methods and Findings, Conclusions) - "methods and findings" is a single subsection.

*At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

*In the Abstract, it would be good to include a (short) statement of what the provision was for the Control arm, so the distinction between intervention and control can be understood.

*In the last sentence of the Abstract Methods and Findings section, please include a brief summary of any of the key limitation(s) of the study's methodology.

*It would be good to update the intext referencing callout at this stage if you can - please change to sequential numbers in square brackets (eg, [1, 2] etc) rather than superscript. If using referencing software this should be quick and easy.

*It would be important to robustly address the concerns raised by reviewer 3, particularly as this reviewer raises a number of points regarding the reliability of the analyses and whether some of the major conclusions drawn in the paper are indeed driven by the data.

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Comments from the reviewers:

Reviewer #1: Alex McConnachie

The following is a statistical review of Korfage et al's report on ACTION, an international, multicentre, cluster randomised trial of the use of advanced care planning for patients with advanced lung and colorectal cancer. Overall, I found the paper to be interesting, and well written. I do have a few comments, but these are generally quite minor.

The cluster randomised trial design is fully appropriate for this intervention, due to the likelihood of contamination. The problem is that participants appear to have known which arm of the trial they were being recruited into, given the very different consent rates (29 vs. 56%) in the two arms. Potentially, two quite different groups of patients may have been recruited into the trial. According to Table 1, the differences do not seem too extreme, plus the analysis includes plenty of adjustments, but with such different recruitment rates, there will always be the doubt that something could be biasing the overall results.

Had participants been asked for consent, and provided baseline measurements, before being told whether their hospital was in the ACP or control arm, this might have allowed some assessment of this differential engagement with the trial. Ideally, one would ask whether the factors associated with participation are the same in ACP hospitals and control hospitals. Is there any information about those who did not take part that could be used in this way?

I was able to replicate the sample size calculation from the information provided, but given that the detectable between-group difference was given a half a standard deviation, it is not clear why the required sample size should reduce when it was decided to change to a different primary outcome.

The analyses are perfectly acceptable. However, in the title of Table 2, the term "causal intercept" was not one I have encountered before (and an internet search did not shed any light). This may need some additional explanation. Another point on reading Table 2, is that it is not obvious whether positive and negative changes for each outcome represent an improvement or a deterioration. Also, though the presentation of the results is generally good, the ICCs for the different outcomes are not reported, as recommended by CONSORT.

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Reviewer #2: Korfage and colleagues report the results of a large cluster-randomised controlled trial to examine the effect of implementing an ACP program in hospitalised patients with advanced cancer in six European countries. Intervention and control group showed no difference with regard to quality of life, the primary outcome, nor with most of the secondary outcomes including hospitalisation rate. Also in the intervention group, very few (even though more than in the control group) of the patients had an AD in their hospital charts.

Congratulation to the authors for this important paper that to me seems methodologically sound, and well written. I have only few and minor suggestions for the sections background, methods and results (see below). I have, however, a major concern that relates to the interpretation of the „negative" findings in the discussion section:

The authors write: „The limited effectiveness of the complex ACP intervention evaluated in this study may be explained by 1) characteristics of the intervention, 2) patients' preferences regarding ACP and Ads or 3) the European context."

In fact there are a number of further possible explanations why this study showed no effect, and given the high attention this large and thoroughly done study is likely to attract, and the possible large impact of reporting a negative outcome in this relatively new and highly sensitive field, it is certainly warranted that these explanations are discussed in detail. In particular, a negative finding of a methodologically sound trial examining the effect of an instrument that has so strong merits as ACP may well cause the authors to take a step back and reconsider their assumptions and design. In my eyes, other passages in the manuscript can and should be shortened (for example the first 8 lines of the background) in order to allow for a thorough critical appraisal of the reasons why this study may have shown no effects. Here is my suggestion of the reasons that ought to be considered:

A. Reasons related to the intervention

1. The authors correctly report that they could not ensure intervention delivery. It would be worthwhile to make this relevant consideration become somewhat more prominent, for example by repeating the corresponding key results.

a. First of all, it seems that conversations as the core of the intervention did take place most of the time (90%), occurred according to protocol (86%), they were extensive in time (93 minutes), contrary to most recommendations, though, they comprised rarely more than one encounter (1.3).

b. However, only 41% of the patients who had ACP conversations proceeded to signing an advance care plan. This is very unusual. Do the authors have any hints from the process evaluation why this was the case? It would be helpful to understand why so many patients did not sign written advance care plans in order to appreciate how much of the intervention was in fact delivered. If it turns out that for practical or cultural reasons, the intervention was insufficiently realised, then this is of central importance for the interpretation of the results and needs to find entry also in the conclusion.

2. There is another important influential factor that warrants discussion. Implementing an ACP program such as Respecting Choices should not be limited to establishing a conversation process between facilitator, patient, and significant others; besides this personal level, there is also an institutional and regional level that logically must be considered if the ultimate goal of ACP that patients' preferences are known and honored is to be achieved.

In particular, Respecting Choices is known to have always pushed both levels, the „systems change" level (institutional / organisational and regional development), and the personal conversation level. The ACTION trial has limited the intervention on the mere personal level. This needs to be discussed here: Why was the decision made? What were the personal, institutional and regional barriers observed in the respective countries? Are there any further indications that a „systems change" would have been necessary to let the intervention develop a positive impact on the clinical encounters?

B. Reasons related to the Study Design

If a study so well done as this one, and testing such an established intervention, does not find the expected group difference, it is warranted to reconsider whether the expectation was legitimate in the first place, for example asking the following questions:

1. Does improvement of quality of life belong to the goals that ACP is intended to reach? The authors correctly state that the ultimate goal of ACP is that patients' preferences are known and honoured when medical decisions have to be made. While I appreciate that relying on the medical team to know my well reflected treatment preferences for such a case may cause a certain sense of reassurance, at least immediately after the planning, personally I am having a hard time to understand how ACP could possibly exert a long-term effect on quality of life. Also, I am not aware of any strong evidence that this is likely to happen. I suggest, therefore, for the authors to discuss whether - in retrospect - the chosen primary (and related secondary) outcomes could really be expected to be affected by ACP even if optimally delivered and implemented.

2. But also with regard to clinical outcomes like hospitalisation: Is ACP likely to change the course of patients with advanced, non-curable cancer? Advance Care Planning, as the authors rightly quote from the EAPC White Paper, allows individuals to reflect, to plan and to document their preferences for future critical treatment decisions that may need to be taken when the now planning individual has become incapable of decision making. Any clinical direct effect of ACP, then, is to be expected (only) if patients are rendered incompetent at some time in the course of their illness AND if at that time medical decisions have to be taken for which the preferences planned and documented in advance can be regarded relevant. In advanced cancer, however, it would not be unexpected that most treatment decisions, even when approaching the very end of life, are made with the competent patient, while these patients become incompetent typically (i.e., with few exceptions) only late in the course of their dying process when any further attempts to sustain life would be futile and therefore medically not indicated (justifiable). Therefore, it would be interesting to learn whether the authors have collected any quantitative or qualitative impressions on whether medical treatment decisions had to be taken at all with study patients incapable of decision making so that an advance care plan, if present, could have become relevant. In any case, it ought to be discussed whether ACP is likely to make an effect in this patient group - unless there is an assumption that ACP indirectly also transforms care planning, i.e. the medical decision making between oncologists and competent, actively participating patients. Such an assumption, however, should also be made transparent in the discussion.

C. „The European context"

Given the strong case that the intervention may not have reached the actual decision making process (as indicated by a low rate of written advance care plans, and by the omisson of any institutional and regional implementation efforts in the sense of a probably necessary change management), and / or that the intervention in its nature may not be suitable to change many of the chosen outcomes, or unfold a relevant effect for the chosen patient population even if perfectly delivered and optimally measured, I would advise to reconsider the „European" argument. Here, the authors generalise their findings to ACP in general, suggesting that in Europe (i.e., for all patient populations in all European countries), there may be a lesser need for ACP because of a lesser rate of over-treatment, compared with the U.S. This is a far-reaching interpretation that in my perception is not warranted by the design nor by the results of this study. Given the alternative good possible explanations reflected above for the negative results found in this study, and the strong body of evidence for both overdiagnosis and overtreatment (and lack of patient-centred care) also in many European countries, this paper does not seem the right place to speculate whether ACP in general may not be a necessary or useful tool for European patients altogether.

Finally, I would suggest that the conclusions do reflect this critial discussion of the study results.

MINOR COMMENTS

Background

I may be wrong but I don't think I understand inhowfar the first 8.5 lines provide a background for this study given that ACP, as defined also by the authors in the following lines, is not an instrument to improve palliative care.

METHODS

The intervention, first paragraph, line 4: What does the number in brackets (14) stand for? Reference # 14 seems not pertinent.

RESULTS

Intervention delivery:

Given the low increase of written advance care plans in hospital charts, it would be interesting to add how many of the 396 patients who had ACP conversations came out of these conversations with written advance care plans. On page 8 (second paragraph) there is an information that „in the intervention group, 147 patients provided their facilitators with a copy of their completed MP forms." Since written advance care plans were one of three intervention components (#2), I would expect them to be reported here, as plain number and proportion.

In order to further help appreciate why hospital admission was not reduced by the intervention, it would be interesting to know how many patients opted for comfort-focused care in section D of their MP form. Were the MP forms analysed by preference?

Primary and secondary outcome measures:

I don't think the reference to the MICE procedure needs to be repeated here.

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Reviewer #3: This is an interesting manuscript about a randomized control trial of advance care planning in patients with advanced cancer. The study's strengths are that it is a large study with 23 sites and is well designed with a cluster-randomized trial. However, my enthusiasm was dampened by several issues. I have the following comments and suggestions:

1. In the background, the authors state that studies of ACP in patients with cancer are scarce. This is not a true statement. There are >1000 pubmed citations with "Advance Care Planning" and "Cancer". Furthermore, the authors cite several papers in their introduction. Please remove or edit this statement.

2. I am concerned about the conclusion that "Alternate approached to support patient-centered end-of-life care in the population are needed". When I think about the causal pathway, ACP is most likely to impact decisions at true end-of-life. These patients were not necessarily followed to death and there are not outcomes about the location of death or quality of decision-making at true end of life. The outcomes in this study were not impacted, so the statement should be specific to those outcomes and not all encompassing end-of-life care, which may have been measured in other ways closer to actual end of life.

3. I have a significant problem with the statement that "When cure is no longer possible, a focus on prolonging life is associated with worse quality of life." When treating metastatic, incurable cancer, we are most often treating with medications that are intended to BOTH prolong life and improve quality of life. While there are times when giving additional chemotherapy at end-of-life is both unlikely to prolong life or to improve quality, this statement is inaccurate the way it is written.

4. Please define the abbreviation ACP in the first use in the introduction.

5. Please clarify who was approached, who delivered the intervention.

6. I am not clear on what the authors mean by the statement that the RC instructors followed the RC First and Advanced Steps training programme together. Please clarify.

7. Please provide more detail on how many conversations were audio-recorded and were these practice conversations vs. conversations with patients with cancer. It would be important to know how the fidelity checklist was used. Did the facilitator have to get all on a certain number of times? This needs much more detail.

8. I would like to see more information on the missingness of the data to ascertain if the multiple imputation is appropriate. Please provider a supplemental with the characteristics of those who did not complete the surveys, as this is common as people approach end of life and may impact interpretation of results. Also, please do a sensitivity analysis with a complete case.

9. There is a large number of people who did not consent. This should be discussed. Also, the recruitment rate for the intervention was much lower than for the control, which doesn't make sense to me in a randomized study. Please explain this finding.

10. It is interesting that the authors state that they did not expect survival differences and yet 44% of people in the intervention died and only 39% in the control group died. This should be evaluated further, and particular attention paid to how this would impact the survey results in terms of missing data and QoL trajectories given that patients typically have a decline in QoL before death. I am not convinced by the P values provided given the small sample size and a clinically meaningful difference.

11. I am concerned about the population differences, in particular lung vs. colorectal cncer between groups. The higher lung cancer in the intervention could results in lower quality of life and the shorter survival in this group given that these diseases have very different prognosis. These groups should be analyzed separately given the lack of balance in the randomization.

12. Please provide explanation of why 10% of the intervention did not receive the ACP. This seems high.

13. There should be more detail on how death was incorporated into the analysis.

14. I struggled with the outcomes selected for the study. Please provide some context as to why and how the authors anticipate that an advance directive conversation would be expected to impact quality of life and emotional functioning at 3 and 6 months if this is not associated with end of life. I recognize that the authors cannot change the data or timing now, but it would be very helpful to understand their thinking in the design and why this was designed in this way. It might even be helpful to provide a conceptual model of impact. I do understand the decision-making outcomes.

15. If possible, provide an explanation of the reason why the one hospital enrolled no patients.

16. Please provide information available of why 13 patient did not complete any questionnaires.

17. Was there an element that was commonly missed in terms of the fidelity? What were the key domains evaluated?

18. The amount of imputed data should be reviewed by a statistician.

19. It is interesting that the decision-making self-efficacy, information provided by nurses/doctors, and rating of care received all declined from baseline. This could warrant comment in discussion.

20. I am very confused by the recruitment rate in the discussion. If the randomization is at a site level, the some received standard of care and it is unclear why they declined. Please provide some literature review of why this might have occurred and/or participation in these types of trials.

21. When the authors discuss the limited effectiveness, they should include some other studies and references to put their findings into context. The discussion should include references where they are making statements about the countries policies as well to verify legitimacy.

22. The discussion of Europe s. US is troubling given that these are strong statements without any literature backing them.

23. I again think the conclusions of alternate approaches is not supported fully by this data, rather that the endpoints chosen are not likely at that time to be impacted by AD.

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Any attachments provided with reviews can be seen via the following link:

[LINK]

25 Jun 2020

Submitted filename: Reply to the editors&reviewers_ACTION_FINAL.docx

Click here for additional data file.

7 Aug 2020

Dear Dr. Korfage,

Thank you very much for submitting your manuscript "Advance care planning in patients with advanced cancer; a six country, cluster-randomized clinical trial" (PMEDICINE-D-20-00632R2) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

In addition, we request that you upload any figures associated with your paper as individual TIF or EPS files with 300dpi resolution at resubmission; please read our figure guidelines for more information on our requirements: http://journals.plos.org/plosmedicine/s/figures. While revising your submission, please upload your figure files to the PACE digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at PLOSMedicine@plos.org.

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We ask every co-author listed on the manuscript to fill in a contributing author statement, making sure to declare all competing interests. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. If new competing interests are declared later in the revision process, this may also hold up the submission. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT. You can see our competing interests policy here: http://journals.plos.org/plosmedicine/s/competing-interests.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

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Senior Editor

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Requests from the editors:

Please adapt the title to fit PLOS Medicine style and replace the “;” with “:”

Is ACTION an acronym? Please introduce on first view. The same goes for EORTC

Please provide participant demographics

Please temper conclusions by including “our results show” or similar

Please can you provide 95% CI along with p values as needed, when quantifying the main results

The data statement needs to be modified as authors cannot be sole contacts for data requests as per PLOS data policy. Please provide institutional or research ethics committee details for data requests.

The author summary needs to be in bullet points

References must be in square brackets and bibliography in Vancouver style please

Methods

Please include your trial registry early in the methods section

Please can you fill the CONSORT reporting guideline and provide this as Supplementary information. Early in the methods section please state that the study has been reported according to CONSORT. Please do not use page numbers when completing the checklist.

Please specifically provide details of informed consent and how it was received from participants

Discussion

Some sections require revision, in line with comments from Ref 2. There are several study design limitations that could have led to the results and therefore it would be cautious to avoid sentences such as “Fourthly, there might be relatively little to gain from ACP in Europe”.

Please add a strengths and limitations section, to discuss the various limitations of your work that could have influenced the findings

The role of the funder and conflicts of interest should be reported in the article meta-data only and removed from the main manuscript document

Specifically, some of the comments in Reviewer 2’s notes are pertinent and require significant revision to your discussion section: “What I am saying is: From the perspective that ACP requires institutional and regional implementation, the ACTION trial’s intervention was never likely to become effective because it lacked two out of three essential components. I understand that for the authors this is a difficult position to report, and the authors do not have to share this view, but since they cooperated with Respecting Choices, and report a negative result, in my eyes it is inevitable to make this possible severe objection clear and transparent in their discussion. Limiting the objection to „countries not familiar with ACP“, in contrast, not only misses but obscures the point”.

“That ACP may prepare for discussions of oncologic treatment is an interesting hypothesis that has no evidence base for this special patient population, certainly not in the paper of Rebecca Sudore et al. quoted by the authors (reference #10).

In my eyes it should be discussed in the limitation section that the ACTION trial may have ended with a negative result because ACP may not be effective in changing quality of life and treatment decisions in the population of patients with advanced cancer since these rarely require treatment decisions to be based on advance care planning”.

“In the light of what can be said about possible shortcomings of the study design (including intervention and target population), this is not a „hypothesis that warrants further study“ but a hypothesis that does not warrant to be made here”

Comments from the reviewers:

Reviewer #1: Alex McConnachie, Statistical Review

I thank the authors for considering my original comments. In general, I am happy with their responses, and have no major concerns.

One comment on the sample size reduction, though. The original calculation was based on detecting a difference of half a standard deviation, or an effect size of 0.5. What is that on the scale of the EF4? Given the association between EF4 and EF10, what would be an "equivalent" difference be for the EF10? Then, given the SD of the EF10, what effect size would that equate to?

Also, it is notable that the ICC observed for the EF10 was smaller than was allowed for at the design stage. This is a good thing, as it should give more power, but does not seem to have been commented on.

Reviewer #2: See enclosure.

Reviewer #3: Thank you for addressing the comments, well done.

Any attachments provided with reviews can be seen via the following link:

[LINK]

Submitted filename: REVIEW PMEDICINE ACTION Trial REVISION.pdf

Click here for additional data file.

13 Sep 2020

Submitted filename: Response to editors & reviewers.docx

Click here for additional data file.

24 Sep 2020

Dear Dr. Korfage,

Thank you very much for re-submitting your manuscript "Advance care planning in patients with advanced cancer: a six country, cluster-randomized clinical trial" (PMEDICINE-D-20-00632R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

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------------------------------------------------------------

Requests from Editors:

Please provide brief participant demographics such as sex, age range etc

Author summary- please remove the phrase “new element”

Page 5 “All competent patients…” do you mean competent to give consent or eligible for study participation? Please clarify

Page 6 “AD” should be introduced as advance directive (?) or other on first view

Page 7 ACTION RC – please define RC on first view

Are the information leaflets, piloted checklists, surveys used in the intervention previously published anywhere? Please provide in text citations or copies as SI files as needed.

Discussion- please add a sentence or two at the start describing what was done

Discussion- Please introduce ICC in text, on first view

Page 16 last paragraph- please change reference 6 to square brackets

Page 17 please include the wordpress link in the bibliography and add a citation, as needed

Please use Vancouver style for the references

Within the CONSORT checklist, please provide details of paragraphs and sections where the information has been provided.

Please call fig 1 "Participant flowchart" and move it to the start of the "results"

CONSORT discourages statistical comparisons of baseline groups (as in table 1). Please remove these.

Please remove "which may to some extent explain the negative results" from the limitations paragraph in the discussion

Please remove the spaces in the square brackets

Please provide full access details for some of the references, for example ref 9, 16 etc

Please provide p values up to three decimal places only. There are some "p<0.0001" in the supplementary tables which should be revised.

Comments from Reviewers:

Any attachments provided with reviews can be seen via the following link:

[LINK]

19 Oct 2020

Dear Ms. Korfage,

On behalf of my colleagues and the academic editor, Dr. Gabrielle Rocque, I am delighted to inform you that your manuscript entitled "Advance care planning in patients with advanced cancer: a six country, cluster-randomized clinical trial" (PMEDICINE-D-20-00632R4) has been accepted for publication in PLOS Medicine.

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Adya Misra, PhD

Senior Editor

PLOS Medicine

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