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Systematic versus on-demand early palliative care: A randomised clinical trial assessing quality of care and treatment aggressiveness near the end of life

European Journal of Cancer, December 2016, Pages 110 - 118

Abstract

Aim

Early palliative care (EPC) in oncology has shown sparse evidence of a positive impact on patient outcomes, quality of care outcomes and costs.

Patients and methods

Data for this secondary analysis were taken from a trial of 207 outpatients with metastatic pancreatic cancer randomly assigned to receive standard cancer care plus on-demand EPC (standard arm) or standard cancer care plus systematic EPC (interventional arm). After 20 months' follow-up, 149 (80%) had died. Outcome measures were frequency, type and timing of chemotherapy administration, use of resources, place of death and overall survival.

Results

Some indices of end-of-life (EoL) aggressiveness had a favourable impact from systematic EPC. Interventional arm patients showed higher use of hospice services: a significantly longer median and mean period of hospice care (P = 0.025 for both indexes) and a significantly higher median and mean number of hospice admissions (both P < 0.010). In the experimental arm, chemotherapy was performed in the last 30 days of life in a significantly inferior rate with respect to control arm: 18.7% versus 27.8% (adjusted P = 0.036). Other non-significant differences were seen in favour of experimental arm.

Conclusions

Systematic EPC showed a significant impact on some indicators of EoL treatment aggressiveness. These data, reinforced by multiple non-significant differences in most of the other items, suggest that quality of care is improved by this approach.

This study is registered on ClinicalTrials.gov (NCT01996540).

Highlights

  • We assessed the impact of systematic versus on-demand early palliative care (EPC) on quality of care outcomes.
  • Use and timeliness of hospice care were more appropriate in the systematic EPC arm.
  • Fewer systematic EPC patients underwent chemotherapy in the last 30 days of life.
  • Percentage of home/hospice deaths was non-significantly higher for systematic EPC.
  • Systematic EPC is advantageous for quality of care and quality of life.

Keywords: Early palliative care, Use of health care services, Care aggressiveness near the end of life.

1. Introduction

Original studies and qualitative and systematic reviews have confirmed the efficacy and effectiveness of palliative care in oncology, with different levels of evidence [1], [2], and [3].

Two main palliative approaches have been identified: ‘End-of-Life’ (EoL) palliative care and early palliative care (EPC). EPC has been suggested as an appropriate health care intervention alongside anticancer treatments to manage cancer patients and is referred to as ‘simultaneous palliative care’ [4], [5], [6], [7], [8], and [9]. The impact of EPC has been studied on: (a) patient outcomes (quality of life [QoL] and psychophysical symptom burden); (b) quality of care and treatment aggressiveness near the EoL and (c) costs [4], [5], [6], [7], [8], and [9].

The effect of EPC on symptom burden and QoL depends on clinical competence and the ability of the palliative care physician and his/her team to manage psychophysical symptoms during the chemotherapy phase. Conversely, the potential impact of EPC on health care resources and treatment aggressiveness near the EoL lies in the capacity of the palliative care team to actively participate in the ‘early’ shared decision-making process (with patient, family and attending oncologist), and also in the degree to which the patient's oncologist accepts the advice of the palliative care specialist [10], [11], [12], and [13].

There is no consistent evidence of the impact of EPC on the above outcomes, and studies focussing on this issue show methodological shortcomings in terms of lack of standardisation of interventions and outcome measures, biased enrolment methods, poor protocol specification, difficulties with protocol adherence, contamination between study groups, insufficient statistical power and notable attrition [1] and [10]. The entire body of scientific knowledge tends to support the usefulness of EPC, and the early implementation of palliative care is fast becoming standard practice for patients with advanced cancer [14]. However, further research is needed to confirm and clarify the real role of EPC. In particular, EPC data needs to be collected on different types of cancer, in different settings and, if possible, from different countries. Once the full potential of EPC has been acknowledged, more appropriate modalities for its integration into standard care can be evaluated [15] and [16].

Different ways of introducing a patient to palliative care services have been identified: spontaneous request for activation from the patient and/or the attending physician on the basis of a referred symptom; request for intervention following symptom identified by a systematic screening tool [17]; automatic activation in patients in a given situation (i.e. first diagnosis of metastatic disease in solid tumours) or on the basis of natural history of a specific cancer and duration of the advanced phase (i.e. first-line chemotherapy for metastatic or inoperable locally advanced pancreatic cancer, or third-line chemotherapy for metastatic breast cancer) [18].

The present study compares on-request activation of EPC and systematic activation for metastatic disease in patients with pancreatic cancer. We chose this particular setting because very little progress has been made in pancreatic cancer patient management. The 5-year survival for pancreatic cancer patients in the United States of America (USA) has only slightly increased over the last 30 years (from 2% to 6%) [19], making it a persistent big killer. Pancreatic cancer currently occupies the 25th position in worldwide prevalence of cancer, with a 5-year prevalence of around 200,000 cases [20].

With regard to global cancer incidence, 2008 estimates ranked pancreatic cancer as 13th of the 20 most commonly diagnosed cancers worldwide [21]. In 2014, pancreatic cancer showed the lowest 5-year survival rate among 30 categorised malignant tumours in the USA [22]. In Europe, pancreatic cancer is currently the 5th cause of death in males (5.4%) and the 4th in females (6.7%) [23].

When the present study was begun, a ‘no palliative treatment’ control arm was considered unethical. We therefore decided to compare an interventional arm in which standard cancer therapy plus best palliative care was systematically performed from the beginning of chemotherapy in patients with advanced pancreatic cancer (systematic EPC) with a standard arm consisting of standard cancer therapy plus on-demand EPC in which a palliative care consultation was requested by oncologists on the basis of symptoms spontaneously reported by patients. Our previous paper focussing on patient outcome as the primary end-point revealed that QoL and symptom burden were significantly in favour of the interventional arm [24]. The present paper describes the results obtained on the use of health care services, a secondary aim of the original study, in the same patient population.

2. Patients and methods

One hundred and forty-nine of the 207 outpatients with advanced and/or metastatic pancreatic cancer enrolled onto the multicenter, randomised ‘systematic versus on-demand early palliative care’ study had died by December 2015. However, complete information on the use of health care services is available for this group. The study design, inclusion criteria, randomisation strategy and results on patient outcomes have already been described in detail [24].

Patients were randomised to receive either ‘standard cancer care plus on-demand EPC’ (standard arm) or ‘standard cancer care plus systematic EPC’ (interventional arm). For interventional arm patients, an appointment was scheduled with a palliative care specialist who discussed a number of health-related areas based on a pre-determined checklist. Patients met a member of the palliative care (PC) team within 2 weeks of enrolment onto the study and were seen every 2–4 weeks thereafter until death. PC appointments and interventions were planned in accordance with general palliative care guidelines [25]. Patients assigned to the standard arm only met the PC team if they (or their families or the attending oncologist) specifically requested an appointment. After the evaluation period (T1 = 12 ± 3 weeks), patients were followed by the PC team as needed.

Once informed consent was obtained (T0), patients completed QoL (primary outcome) and mood questionnaires, as described elsewhere [24]. After the patient's death (T2), information on the use of health care services and EoL care, including anticancer therapy, referral to hospice, hospital admissions, emergency department visits and the date and place of death (secondary outcomes), were collected.

Data on frequency, type and timing of chemotherapy administration, use of health care resources (emergency department visits/hospital admission/referral to hospice and unit days) and date and place of death were retrieved from medical records or proxy reports and recorded using a case report form designed for the study. In particular, the following information was noted: frequency and date of palliative care visits in each treatment arm; type, setting and timing of all chemotherapy (intravenous and oral agents, lines of therapy, start and end date of administration); use of radiotherapy, number of hospitalisations, emergency department visits and use of hospice services (including number of days spent in hospice from study enrolment to death or number of days in home palliative care program); and date and place of death.

The study was carried out in accordance with the principles laid down in the Declaration of Helsinki and after full Ethics Committee approval of the participating centres. All patients provided written informed consent.

2.1. Statistical analysis

The objective of this secondary analysis was to examine the effect of palliative care intervention on the use of health care services (referral to hospice, hospital admission, emergency department visits), place of death, overall survival (OS) and use of chemotherapy near the EoL. Continuous variables were summarised by descriptive statistics (number of cases, mean, standard deviation [SD], median, minimum, maximum) and categorical variables were summarised using counts of patients and percentages. Differences between study groups in clinical outcomes were assessed with the chi-square test for categorical variables and the Student's t-test or non-parametric ranking statistic (median test) for continuous variables. Logistic regression analyses were performed, adjusting for baseline characteristics (age, gender, marital status, performance status) to examine the effect of EPC on the use of chemotherapy and health care measures. OS was defined as the time from the date of randomisation to the date of death from any cause. OS was estimated with Kaplan–Meier product-limit method and corresponding 95% confidence intervals (CI) was calculated using the Greenwood method. The analyses were performed on an intention-to-treat population that fulfilled eligibility criteria. All tests were two-sided at a significance level of 0.05. No interim analysis was planned. No multiplicity test correction was performed.

All statistical analyses were performed using SAS Statistical Software version 9.4 (SAS Institute, Cary, NC, USA).

3. Results

Two hundred and seven patients with advanced and/or metastatic pancreatic cancer recruited in 21 Italian centres between October 2012 and February 2015 were considered for the study. Twenty-one (9.9%) patients were excluded from the study, leaving 186 eligible for analysis (89 in the standard arm and 97 in the interventional arm; Fig. 1). The most frequent reason for exclusion after informed consent was non-administration of chemotherapy, mainly due to patient refusal or rapid worsening of clinical conditions. Of the 186 patients, 149 had died at the time of the study analysis in December 2015. The twelve-month OS probability was 22.4% (95% CI 13.0–31.7) for the interventional arm and 12.3% (95% CI 4.8–19.9) for standard arm patients (p = 0.288). Median OS was 6.6 months (95% CI 4.4–8.1) for the interventional arm and 5.7 months (95% CI 4.8–7.6) for the standard arm. Patients who had died were evaluated for their use of health care services. Baseline characteristics of patients enrolled in the two arms were superimposable (Table 1).

Fig. 1

Fig. 1

Flow-chart of the study: patient recruitment, treatment and analysis. *T0: baseline; T1: 12 ± 3 weeks; T2: after patient’s death

 

Table 1

Baseline characteristics of the study participants (n = 149).

 

Standard arm (N = 73) Interventional arm (N = 76) P
N (%) N (%)
Median age, years (range) 66 (37–84) 68 (43–85) 0.268
Gender
 Male 41 (56.2) 44 (57.9)
 Female 32 (43.8) 32 (42.1) 0.832
Marital status
 Married 49 (77.8) 54 (76.1)
 Single 4 (6.4) 6 (8.4)
 Divorced or separated 5 (7.9) 4 (5.6)
 Widowed 5 (7.9) 7 (9.9) 0.963
 Unknown/missing 10 5
ECOG performance status
 0 39 (53.4) 39 (52.7)
 1 30 (41.1) 29 (39.2)
 2 4 (5.5) 6 (8.1) 0.744
 Unknown/missing 0 2
Assessment of mood symptomsa
HADS anxiety subscale
 Normal (≤7) 41 (57.7) 41 (54.7)
 Abnormal (>7) 30 (42.3) 34 (45.3) 0.709
 Unknown/missing 2 1
HADS depression subscale
 Normal (≤7) 43 (60.6) 54 (72.0)
 Abnormal (>7) 28 (39.4) 21 (28.0) 0.145
 Unknown/missing 2 1
Scores on quality of life measures Mean value (SD) Mean value (SD)
 FACT-Hep scoreb 116.7 (23.6) 118.8 (20.1) 0.576
 HCS scorec 49.7 (9.3) 50.7 (9.0) 0.483
 TOI scored 81.3 (18.4) 83.4 (16.6) 0.478

a The HADS consists of 2 subscales (one for symptoms of anxiety and one for symptoms of depression). Subscale scores range from 0 to 21 (0 = no distress, 21 = maximum distress); a score >7 indicates clinically meaningful anxiety or depression.

b FACT-Hep scores ranged from 0 to 180 (higher scores indicated fewer symptoms: the higher the score, the better the QoL).

c HCS (Hepatobiliary Cancer Subscale) scores ranged from 0 to 72.

d TOI (Trial Outcome Index) scores ranged from 0 to 128. SD, standard deviation.

The number of PC visits made is reported in Table 2. The mean number of PC visits for interventional arm patients was 6.89 (SD 4.88, range 1–16) compared to 1.81 (SD 2.98, range 0–10) for those in the standard arm (P < 0.0001). Notably, however, a high number of PC visits was also registered within the standard arm group: 34/73 (46.6%) patients had 132 PC consultations.

Table 2

Palliative care intensity for standard and interventional groups.

 

Mean and median number of palliative care visits
Standard arm (N = 73) Interventional arm (N = 76) P
Palliative care clinic visits (T0–T1)
 Median value (range) 0 (0–8) 4 (1–11) <0.0001
 Mean value (SD) 0.70 (1.43) 4.16 (2.22) <0.0001
Palliative care clinic visits (overall)
 Median value (range) 0 (0–10) 6 (1–16) <0.0001
 Mean value (SD) 1.81 (2.98) 6.89 (4.88) <0.0001
Distribution of palliative care clinic visits
Standard arm (N = 73) Interventional arm (N = 76)
No. (%) No. (%)
Palliative care clinic visits (T0–T1)
 None 50 (68.5) 0
 1 10 (13.7) 15 (19.7)
 2 8 (11.0) 6 (7.9)
 3 1 (1.4) 6 (7.9)
 4 2 (2.7) 13 (17.1)
 ≥5 2 (2.7) 36 (47.4)
Palliative care clinic visits (overall)
 None 39 (53.4) 0
 1 10 (13.7) 15 (19.7)
 2 10 (13.7) 6 (7.9)
 3 1 (1.4) 3 (3.9)
 4 1 (1.4) 6 (7.9)
 ≥5 12 (16.4) 46 (60.6)

SD, standard deviation.

With regard to use of hospice services, two assessed indices were in favour of the interventional arm (Fig. 2): median and mean number of admissions to hospice (P = 0.006 and P = 0.001, respectively) and median and mean duration of hospice stay (14 days range 1–40) for standard arm versus 20 days (range 1–76) for the interventional arm, and 14.9 (SD 11.1) versus 25.2 (SD 24.0) days, respectively (P = 0.025 for both indices; Table 3). Adjusting for baseline characteristics (age, gender, marital status and performance status), the number of patients referred to hospice did not differ significantly between the two arms. Interventional arm patients died at home or in hospice more often than those in the standard arm (77.8% versus 66.7%, respectively; P = 0.102), but this difference was not significant. However, the former group underwent a significantly lower rate of chemotherapy in the last 30 days of life than those receiving standard care (18.7% versus 27.8%, respectively; P = 0.036). The frequency of hospitalisations and emergency department visits was not significantly different between the two groups (Table 3).

Fig. 2

Fig. 2

(A) Percentage of patients in each arm as a function of number of hospice admissions. (B) Distribution of patients in each arm as a function of the total number of days spent in hospice from enrolment to death.

 

Table 3

Use of health care services.

 

Standard arm N (%) Interventional arm N (%) P a
Chemotherapy administration
 Any chemotherapy ≤ 14 days before death 8/72 (11.1) 10/75 (13.3) 0.826
 Any chemotherapy ≤ 30 days before death 20/72 (27.8) 14/75 (18.7) 0.036
Hospitalisation
 Any admission from enrolment to death 53/72 (73.6) 51/75 (68.0) 0.417
 Any admission ≤ 30 days before death 40/72 (56.3) 38/75 (50.7) 0.539
Emergency department visits
 Any ED visit from enrolment to death 30/71 (42.2) 29/75 (38.7) 0.891
 Any ED visit ≤ 30 days before death 20/71 (28.2) 20/75 (26.7) 0.729
Place of death
 Home 17/72 (23.6) 22/72 (30.6)
 Hospice 31/72 (43.0) 34/72 (47.2)
 Hospital 22/72 (30.6) 15/72 (20.8)
 Nursing home 2/72 (2.8) 1/72 (1.4) 0.702
 Home + hospice 48/72 (66.7) 56/72 (77.8)
 Hospital + nursing home 24/72 (33.3) 16/72 (22.2) 0.102
Hospice services
 No admission to hospice 40/73 (54.8) 42/76 (55.3) 0.933
 Admission to hospice ≤7 days before death 22/73 (30.1) 22/76 (28.9)
 Admission to hospice >7 days before death 11/73 (15.1) 12/76 (15.8)
 Admission to palliative care program (home palliative care) 22/71 (31.0) 28/73 (38.4) 0.298
Mean value (SD) Mean value (SD)
Admission to hospice before death
 Number of total admissions 0.97 (0.37) 1.38 (0.64) 0.001
 Days in hospice 14.9 (11.1) 25.2 (24.0) 0.025
Admission to palliative care program (home palliative care)
 Days on palliative care program 29.0 (29.5) 43.2 (68.5) 0.380
Median value (range) Median value (range)
Admission to hospice before death
 Number of total admissions 1 (0–2) 1 (1–3) 0.006
 Days in hospice 14 (1–40) 20 (1–76) 0.025
Admission to palliative care program (home palliative care)
 Days on palliative care program 19 (1–105) 15 (1–289) 1.000

a Adjusted for age, gender, marital status and performance status.

ED, emergency department; SD, standard deviation.

4. Discussion

A previous paper by our multicenter group described the positive impact of systematic EPC compared to on-demand EPC on patient outcomes, especially QoL and symptom burden [24]. The present work reports on the effect of systematic EPC on quality of care issues. Earle et al.[26] described the following as indicators of low quality care: overuse of chemotherapy very near death, underuse of hospice services and misuse of treatments resulting in high rates of emergency room visits, hospitalisations or intensive care unit (ICU) stays for terminal patients.

Many of the above indicators are a consequence of EoL care practices. It has been hypothesised that EPC can influence such indicators by making an impact on the decision-making processes. However, contrasting results have been reported for care aggressiveness measured by EoL care indicators. Teno et al.[27] observed an increase in the use of hospice services and fewer hospital deaths in Medicare hospice program beneficiaries from 2000 to 2009, but also reported a more widespread use of ICUs, mechanical ventilation and health care transitions near death. Wright et al.[28] evaluated care aggressiveness at the EoL and the use of hospice in a population of older patients with ovarian cancer. Although hospice use increased between 1997 and 2007 and terminal hospitalisation decreased, both significantly, the number of ICU admissions, hospitalisations, and repeated emergency department visits also rose. The more frequent referral to hospice during the last days of life was not intended as a substitute for intensive EoL care, but rather was a means to manage death after the failure of mainly aggressive interventions. Although terminal hospitalisations decreased, the use of hospital-based services near death increased significantly.

The three major randomised studies performed on EPC showed contrasting results with regard to its impact on quality of care data. In the work by Bakitas et al. [29], no differences were observed between the interventional and standard arms with respect to the use of health care services, whereas studies by Temel et al. and Zimmermann et al[30] and [31] reported some differences in this area. The study by Temel et al[30] revealed an advantage for the interventional arm in the following care indicators: chemotherapy ≤14 days before death, no hospice care or admission to hospice ≤3 days before death and documented patient resuscitation preferences. Although the study did not have the statistical power to assess specific indicators of EoL care aggressiveness, the analyses of various use of resources suggested an improvement in quality of care. Greer et al.[32] reported a reduction in the intravenous administration of chemotherapy. The awareness of prognosis was also assessed in another study by Temel et al. [33] and was found to be superior in the interventional arm.

In the cluster randomised study by Zimmermann et al. [31], the use of health services did not undergo multifactorial assessment. However, some items considered showed an advantage of the interventional arm over the standard arm, i.e. higher numbers of PC unit admissions (7.5% versus 0%), inpatient PC consultations (7.9% versus 0.9%), PC home nursing (17.1% versus 3.0%) and home PC physician visits (7.9% versus 3.0%).

In works by both Temel et al. and Zimmermann et al. [30] and [31] the number of PC visits registered for standard arm patients was much lower than that of the same group in our study. In particular, 10/77 (13.5%) standard arm patients in study by Temel et al. underwent 13 PC visits over the 12 weeks of the study compared to 47 visits in 23/233 (9.8%) patients in trial by Zimmermann et al. During the T0–T1 period in our study, 23/73 (31.5%) standard patients underwent 47 PC visits. Our data bridge the gap somewhat between the 2 study arms probably because over time the use of EPC has increased in clinical practice and oncologists are now much more familiar with the approach. Recently, a retrospective population-based cohort study by Jang et al.[34] using administrative data examined the impact of PC consultation on aggressiveness of EoL care in 5381 patients with metastatic pancreatic cancer. A higher number of PC consultations were associated with less aggressive EoL care. However, as median survival was 75 days, this study can probably be considered as an evaluation of EoL PC rather than of EPC intervention. Preliminary findings from a multicenter randomised Danish PC trial [35] were presented at the 14th World Congress of the European Association for Palliative Care in Copenhagen. The authors reported negative results on all the items studied, hypothesising a number of causes for such findings including patient selection, choice of outcomes, analytic strategy and type of intervention.

Our study has some limits. First, it was conducted in Italy, where EPC consultation referrals, even in a clinical study, have to be validated by the attending oncologist. Furthermore, patient awareness about prognosis is somewhat limited and unreasonable confidence in the effects of chemotherapy is often high in EoL situations, rendering this phase of the disease more difficult to manage. This may also have happened in our study on EPC. In addition, some of the centres taking part were small community centres unaccustomed to performing clinical palliative care research. Despite having a strong prospective randomised controlled design, our study did not have the statistical power to examine the specific indicators of aggressiveness in EoL care. Furthermore, our EPC interventions were managed by a single PC physician rather than a full multidisciplinary PC team. Finally, the very high number of palliative care visits in the standard arm, when compared with that of previously conducted PC trials, may have reduced the difference between the standard and interventional arms, leading to an underestimation of the results of the systematic EPC approach.

Our study also has a number of strengths. To our knowledge, it is the first European work to confirm the results of important North American trials. Our multicenter study also involved small non-academic/non-research centres. Some elements that we previously regarded as ‘weaknesses’ may, on the contrary, have led to an underestimation of the effectiveness of systematic EPC, thus lessening the overall impact of our results.

In conclusion, our study suggests that EPC has a positive impact on the aggressiveness of some health care items in EoL care. More research is needed to clarify optimal types and timing of EPC interventions [36]. However the risk of ‘contamination’ between study arms is destined to grow as oncologists activate on-demand EPC with ever-increasing frequency. Thus, it may become difficult to carry out studies of this type in the future.

Funding

This trial was partially supported by a research grant from the Italian Ministry of Health (RF-2011-02350971). The study sponsor was involved neither in the study design nor in the collection, analysis and interpretation of data. The study sponsor did not provide writing support for the report. All authors had full access to all the data in the study. The corresponding author had the final responsibility to submit for publication.

Contributors

Conception and design: Marco Maltoni, Emanuela Scarpi, Chiara Maria Broglia and Oriana Nanni.

Collection and assembly of data: Marco Maltoni, Emanuela Scarpi, Chiara Maria Broglia, Oriana Nanni, Monia Dall’Agata, Stefania Schiavon, Vittorina Zagonel, Antonella Galiano, Claudia Biasini, Luigi Cavanna, Daris Ferrari, Carla Codecà, Chiara Maria Broglia, Paolo Pedrazzoli, Roberto Bortolussi, Ferdinando Garetto, Luisa Fioretto, Maria Teresa Cattaneo, Alice Giacobino, Massimo Luzzani, Giovanna Luchena, Sara Alquati, Silvia Quadrini, Elisabetta Sansoni, Giovanni Luca Frassineti, Andrea Casadei Gardini, Manlio Monti.

Data analysis and interpretation: Marco Maltoni, Emanuela Scarpi, Oriana Nanni.

Manuscript writing: All authors.

Final approval of manuscript: All authors and members of Early Palliative Care Italian Study Group and co-authors of the paper.

Conflict of interest statement

None declared.

Acknowledgement

This trial was partially supported by research grant no. RF-2011-02350971 from the Italian Ministry of Health. This study is registered on ClinicalTrials.gov (NCT01996540).

The authors also thank Cristiano Verna and Laura Lotito for editorial assistance.

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Footnotes

r Department of Medical Oncology, IRST IRCCS, Meldola, Italy

s Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy

t Palliative Care and Hospice Unit, AUSL Romagna, Cesena, Italy

u Psychooncology Service, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy

v Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology IOV – IRCCS, Padua, Italy

w Medical Oncology Unit, Oncology-Hematology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy

x Palliative Care Unit, Oncology-Hematology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy

y Medical Oncology Unit, San Paolo Hospital, Milan, Italy

z Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

aa Medical Oncology Unit, Aviano National Cancer Institute, Aviano, Italy

ab Medical Oncology Unit, Presidio Humanitas Gradenigo, Turin, Italy

ac Coordinamento Cure Palliative (supported by F.I.L.E., Leniterapia Italian Foundatio), Florence, Italy

ad Medical Oncology Unit, Oncology Department, S. Maria Annunziata Hospital, Florence, Italy

ae Palliative Care Unit, Oncology Department, L. Sacco Hospital, Milan, Italy

af Oncology Unit, Ospedale degli Infermi, Ponderano, Italy

ag Medical Oncology, Department of Medicine, E.O. Galliera Hospitals, Genoa, Italy

ah Oncology Unit, Sant’Anna Hospital, Como, Italy

ai Palliative Care Unit, Arcispedale S. Maria Nuova – IRCCS, Reggio Emilia, Italy

aj Oncology Unit, SS Trinità Hospital Sora, ASL Frosinone, Frosinone, Italy

ak Oncology Unit, ULSS 12 Veneziana, Venice, Italy

al Hospice Nazareth, Mestre, Italy

am Palliative Care Unit, Casale Monferrato, ASL Alessandria, Italy

an Medical Oncology Unit, Istituti Ospitalieri, Cremona, Italy

ao Palliative Care, Pain Therapy and Rehabilitation Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

ap Palliative Care Unit Ravenna, AUSL Romagna, Italy

a Palliative Care Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy

b Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy

c Pain Therapy and Palliative Care Unit, Veneto Institute of Oncology IOV – IRCCS, Padua, Italy

d Medical Oncology Unit, Oncology–Hematology Department, Guglielmo da Saliceto Hospital, Piacenza, Italy

e Medical Oncology Unit, San Paolo Hospital, Milan, Italy

f Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

g Palliative Care and Pain Therapy Unit, Aviano National Cancer Institute, Aviano, Italy

h Medical Oncology Unit, Presidio Humanitas Gradenigo, Turin, Italy

i Medical Oncology Unit, Oncology Department, S. Maria Annunziata Hospital, Florence, Italy

j Palliative Care Unit, Oncology Department, L. Sacco Hospital, Milan, Italy

k Oncology Unit, Ospedale degli Infermi, Ponderano, BI, Italy

l Palliative Care, Department of Geriatric, Orthogeriatric and Rehabilitation Frailty Area, E.O. Galliera Hospitals, Genoa, Italy

m Oncology Unit, Sant’Anna Hospital, Como, Italy

n Palliative Care Unit, Arcispedale S. Maria Nuova – IRCCS, Reggio Emilia, Italy

o Oncology Unit, SS Trinità Hospital Sora, ASL Frosinone, Italy

p Department of Clinical and Experimental Oncology, Medical Oncology Unit 1, Veneto Institute of Oncology IOV – IRCCS, Padua, Italy

q Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy

Corresponding author: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, FC, Italy. Fax: +39 0543 739290.


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