Top Practice Changing Articles of 2018 Alison Murray Amane Abdul-Razzak

Objective

▪ To discuss 5 potentially practice-changing papers in the field of palliative care: ▪ Describe papers (i.e., design, population, interventions) ▪ Discuss strengths and limitations and relevance to practice

▪ Interactive discussion

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Faculty/Presenter Disclosure

• Faculty: Amane Abdul-Razzak

• Relationships with financial sponsors: • Grants/Research support: N/A • Speakers Bureau/Honoraria: Purdue Pharma: honoraria for acting as a moderator for

educational events • Consulting Fees: N/A • Patents: N/A • Other: N/A

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Faculty/Presenter Disclosure

• Faculty: Alison Murray

• Relationships with financial sponsors: - Grants/Research support: N/A

- Speakers Bureau/Honoraria: N/A

- Consulting Fees: N/A

- Patents: N/A

- Other: Wellspring Calgary- a non profit organization which supports people with cancer.

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Search Strategy

▪ PubMed search terms: palliative care OR cancer pain OR "advanced care planning" or supportive care

▪ Article types: clinical study, clinical trial, controlled clinical trial, guideline, meta-analysis, observational study, pragmatic clinical trial, randomized controlled trial, systematic reviews

▪ Articles published from March 1 2018 to March 31, 2019

▪ English language and Human subject filters

▪ Yielded 3906 results

▪ Abstracts reviewed by one person (AA or AM); 29 articles selected to review together

▪ 5 articles selected as top papers

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Selection Strategy

▪ Factors considered: ▪ Study design (e.g., meta-analysis/SR>RCT>non-randomized

trial>prospective observational>retrospective/case series ▪ Relevance to a palliative care specialist/consultant ▪ Novelty ▪ May change practice (or at least consideration of change of

practice or maybe support what you’re already doing)

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The Question:

What is the clinical effectiveness and safety of radiofrequency ablation, with or without vertebroplasty, in patients with painful spinal metastases?

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▪ Study Design: systematic review1 ▪ Original studies assessed for quality and risk of bias by 2 members of the

research team using the Institute for Health Economics (IHE) Risk of Bias checklist for case series

▪ GRADE categories to synthesize and rank strength of evidence for effectiveness and safety

▪ Funding: No external funding

▪ Time Period: earliest records to December 2016

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▪ Who was Studied/Original Studies Included: ▪ Patients with solitary fracture-related vertebral metastases not

eligible for surgery OR in cases where symptoms did not improve despite maximal radiation dose

▪ Patients experienced severe pain unresponsive to previous treatments (analgesics, chemotherapy or radiation treatment)

▪ RCTs, nonrandomized controlled trials, prospective and retrospective case series (if retrospective then sample >30 patients)

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Search Strategy

▪ Systematic literature search: MEDLINE, Embase, Cochrane Library, PubMed and CRD (DARE, NHS-EED, HTA)

▪ No specific study design or time period filters

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▪ Who was Excluded: studies published in languages other than English or German

▪ How many patients: ▪ Total of 9 original studies (4 prospective; 5 retrospective) ▪ N=583

▪ Intervention: ▪ Variety of radiofrequency ablation (RFA) systems used ▪ 437 patients (72.4%) received vertebroplasty/kyphoplasty following RFA

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▪ Follow-up: variable ▪ From 24-48 hrs to up to 60 months ▪ One study did not report follow-up time

▪ End Points:

▪ Could not assess strength of evidence (GRADE) for clinical effectiveness due to lack of trials with comparative treatment arm ▪ Effectiveness for Pain Reduction:

▪ In 3/4 prospective studies pain instruments used (visual analogue scale or numeric pain rating scale) and reported significant pain relief relative to baseline

▪ In 1 prospective study only proportion of patients reporting pain relief cited (52.8%) without use of any pain instrument

▪ In retrospective studies: variable outcome measures; all showed significant pain relief (largest retrospective of 250 patients did not report use of a specific pain instrument)

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▪ End points (con…): ▪ HrQoL: assessed by 2 prospective studies

▪ One study used Functional Assessment of Cancer Therapy-General 7 (FACT-G7) and Functional Assessment of Cancer Therapy Quality-of-Life Measurement in Patients with Bone Pain (FACT-BP): ▪ FACT-G7 improvement by 4.8 and 5.2 points (/28) at 1 and 3 months respectively ▪ FACT-BP improvement of 14.7 and 16.3 points (/64) at 1 and 3 months respectively

▪ Two included the Owestry Disability Index and found statistically significant improvements (improvement from severe to moderate disability in 1 study; 30% improvement in another study)

▪ Safety: ▪ GRADE strength of evidence “very low” due mainly to missing data for

control groups and overlapping samples of patients in 2 studies ▪ Overall, of 583 patients included in all studies, adverse events were reported in

105 (18%) ▪ Most frequently these were:

▪ Increased pain and numbness ▪ Post-procedure radicular symptoms

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▪ Limitations: ▪ Using IHE checklist for case series, 5 studies had high risk of bias and 4 had

moderate risk of bias ▪ GRADE strength of evidence “very low” for safety outcomes and unable to

assess for effectiveness ▪ Variability in technique/technology used across studies

▪ Can we anticipate a similar treatment effect across all of these interventions? I don’t know…

▪ Variable cointerventions (e.g., analgesia, radiation therapy) just prior to or after RFA

▪ No comparative studies included (i.e. no RCTs) ▪ No information on minimally clinical important difference (MCID) for many of the

measures used ▪ No discussion of attempts to assess for publication bias or selective outcome

reporting bias (e.g., searching grey literature, funnel plots/quantitative measures, contacting others to ensure full disclosure of results)

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▪ Other Relevant Studies: ▪ “CAFE” RCT in 2011 (n=343) compared balloon kyphoplasty to

non-surgical management for patients with pathologic vertebral compression fractures2

▪ Non-surgical management included analgesia, bedrest, physio, bracing, rehabilitation, walking aids, radiation therapy, other anti-tumour treatment at discretion of treating physician)

▪ Statistically and clinically significant reduction in Roland Disability Questionnaire in intervention arm (-8.4 mean diff; p<0.0001) (MCID=2)

▪ RFA as a useful add-on in these cases?

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▪ Summary and Implications: ▪ Potentially promising to think of RFA for patients with painful spinal bony metastases but

evidence base is weak

▪ Particularly when radiation, surgery, off the table

▪ As an adjunct to RFA?

▪ Future study ideas: ▪ RCT on RFA vs “standard care” (i.e. analgesia, non-pharmacologic measures) in patients who

are not candidates for further radiation or surgical treatment ▪ RCT of (RFA + vertebroplasty/kyphoplasty) vs. RFA alone

▪ Your thoughts?

▪ Have you referred for RFA for spinal bony metastases?

▪ If not, would you consider it now?

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The Question:3

In patients with malignant pleural effusion, is talc administered through an indwelling pleural catheter more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone?

“The IPC-Plus trial”

▪ Funding: unrestricted grant from Becton Dickinson (BD) (not same as the Steritalc® company; Boston Medical Products but supplied PleurX catheters and drainage bottles for study participants)

▪ Time Period: June 2012 to December 2016 ▪ Setting: 18 secondary and tertiary care centres in the UK ▪ Study Design: Randomized, placebo-controlled, single-blind, parallel-group

trial ▪ Centralized computer-based randomization by Sealed Envelope Ltd. 1:1 ratio with

minimization variables: ▪ Volume of pleural fluid removed (≤1999mLs vs ≥2000mLs) ▪ Malignancy subtype: (ovarian & breast) vs. mesothelioma vs. other ▪ Day 10 (randomization day) CXR appearance: no trapped lung vs. some trapped

lung but still meets inclusion criteria

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▪ Who was Studied: ▪ Patients with symptomatic pleural effusion and elected treatment with

indwelling pleural catheter ▪ Expected survival of >2 months ▪ Expected ECOG of ≤ 2 after fluid drainage (up and about >50% of waking

hours; able to perform all self-care)

▪ Who was Excluded: ▪ Age <18 years ▪ Extensive lung entrapment or fluid loculation ▪ Ipsilateral attempt at pleurodesis within previous 8 weeks ▪ Any contraindication to trial procedure

▪ How many Patients: 154 (with appropriate sample size calculation for 90% power at a 5% significance level)

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▪ Intervention: ▪ Talc group: 4g of sterile graded talc made into a slurry with 50mL of 0.9% NaCl

solution and injected through IPC ▪ Placebo group: 50mL of 0.9% NaCl solution injected through IPC ▪ Patient participant blinding: use of opaque syringes; patient positioning so that

IPC/syringes not readily visible—trial team aware of participant assignments (single blinded)

▪ Allocation concealment: remote randomization

▪ Follow-up: up to 70 days after randomization or until death (whichever first)

▪ Primary Outcome: proportion of participants with pleurodesis at day 35 after randomization ▪ Successful pleurodesis defined as:

▪ <50mL of fluid drained on three consecutive occasions through the IPC; and ▪ if CXR taken after these drainages showed less than 25% opacification of the

hemithorax due to suspected fluid.

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▪ Study enrollment and randomization: ▪ 250 participants enrolled and had IPC inserted with local anesthesia

▪ Maximal fluid drainage occurred at time of catheter placement as limited by symptoms

▪ Discharged home same day, and received at least three further drainages (at outpatient clinic or trial centre or with community nurse), limited to 1L each, before review at day 10

▪ At day 10: one more drainage at trial centre followed by CXR: ▪ Patients who had <75% pleural apposition or >1/3 opacification due to fluid (use of

thoracic US) considered ineligible for randomization

▪ 154 participants underwent randomization (talc=78; placebo=76): ▪ 32 excluded for extensive lung entrapment ▪ other common reasons for exclusion: too unwell; issues with IPC; 6 died before

randomization

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▪ Results: ▪ Intention to treat principle: all participants with observed outcome

included in analysis according to assigned trial group ▪ 9 excluded from talc group; 6 excluded from placebo group (insufficient

data to calculate primary outcome at day 35) ▪ 20 participants withdrew during course of trial (10 from each group) ▪ Minimization variables used as covariates in regression models ▪ Primary outcome analyzed with use of time-to-event regression model ▪ Primary outcome: 30/69 (43%) in talc group vs. 16/70 (23%) in placebo

group has successful pleurodesis (HR 2.20; 95% CI 1.23 to 3.92; p=0.008)

▪ Participants well matched at baseline except for imbalance among patients treated with LMWH

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▪ Secondary Outcomes: ▪ At day 70: 35/69 (51%) in talc group compared with 19/70 (27%) in placebo group experienced successful pleurodesis

(HR 2.24; 95% CI 1.31-3.85; p=0.003)

▪ Median volume of fluid between randomization and day 70 (p=0.36): ▪ Talc group: 1350mL (IQR 340-5680) ▪ Placebo group: 3640mL (IQR 845-7605)

▪ Quality of Life: ▪ Better QoL in talc group at all time points ▪ QLQ-C30: mean difference over whole trial 6.9 points (p=0.02) (“little change”) ▪ EQ-5D-5L: mean difference over whole trial 0.07 points (p=0.04) (unclear clinical significance, score can range from -0.285 to 1; 0=dead;

1=full health)

▪ Symptoms: ▪ Chest pain (0-100mm VAS) treatment effect -5.4 points (p=0.007) ▪ No significant difference for dyspnea

▪ Effusion size and complexity: no significant between-group difference (US assessment)

▪ Duration of hospital stay: no significant difference between groups in number of hospital days

▪ Mortality and adverse events: no significant difference between groups

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▪ Limitations: ▪ Follow up only up to 70 days ▪ 96/250 enrolled patients excluded prior to randomization—perhaps a

comment on external validity (e.g., cannot apply to those with poor functional status)

▪ Definition of pleurodesis did not attempt to assess visceroparietal adhesion more formally (e.g., with use of ultrasound) ▪ Currently no consensus on how to evaluate pleurodesis

▪ Although expected survival of >2 months was part of inclusion criteria, at 35 days had 58% drop out (death) in talc group and 39% in placebo group ▪ May impact validity of results

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▪ Other Relevant Study: ▪ AMPLE trial (JAMA 2017)4 IPC vs talc pleurodesis (n=146)

▪ Primary objective: to determine if IPCs reduce total hospitalization days compared to talc pleurodesis

▪ Found a median of 10 vs 12 days hospitalization in IPC and talc pleurodesis groups respectively (p=0.03) ▪ Clinical significance of 2 day difference?

▪ Secondary outcomes: ▪ Fewer patients in IPC group required further ipsilateral

invasive pleural drainages (3 vs 16 patients; p=0.001) ▪ No differences in breathlessness or QoL (both groups had

significant improvements) or survival

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▪ Summary and Implications: ▪ Talc administered through IPC increases likelihood of successful

pleurodesis compared to IPC alone (by approximately two-fold) in patients without lung entrapment

▪ No adverse events seen in talc group (e.g., blockage of IPC, fluid complexity, drainage issues)

▪ May improve symptoms (i.e. chest pain) and QoL—need further studies to investigate

▪ Did not attempt to remove IPCs if fluid accumulation ceased (would be compelling if talc group was able to have IPCs removed more often…)

▪ Does talc pleurodesis occur in your centre? What about talc through an IPC?

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The Questions:5

Primary: What is the prevalence of femoral DVT in people with advanced cancer admitted to a specialized palliative care unit (SPCU)?

Secondary:

▪ What are the predictors of femoral DVT in this population?

▪ Are femoral DVTs associated with shorter survival?

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▪ Study Design: ▪ Prospective, multicentre, longitudinal observational study

▪ Funding: National Institute for Health Research (England)

▪ Time Period: June 20, 2016 to October 16, 2017

▪ Who was Studied: ▪ > 18 yo with advanced cancer admitted to one of 5 specialized palliative

care units (four hospices, one pall care unit)

▪ Who was Excluded: ▪ Prognosis ≤ 5 days ▪ Insufficient English or Welsh

▪ How many Patients: 343 (273 with evaluable scans)

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▪ Study Procedures: ▪ Bilateral bedside femoral and popliteal vein ultrasound scans carried out by one

of five trained research nurses (received 2 day training course for purpose of study and additional training 3 months into study because of issues with image quality/technique)

▪ Data gathered on clinical symptoms/signs (leg edema; prominent veins; tenderness along distribution of deep venous system; calf swelling with ≥ 3cm calf diameter discrepancy measured 10 cm below tibial tuberosity; pleuritic chest pain or breathlessness)

▪ Ultrasound completed weekly along with data collection on symptoms/signs for maximum of 3 weeks (or until discharge or death)

▪ Follow-up: until death

▪ End Points: ▪ Primary: prevalence of DVT within 48 hours of admission to SPCU ▪ Select secondary: clinical factors predictive of VTE including survival; 3-week

incidence of new VTE during admission

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▪ Results: ▪ 273 patient scans evaluated, 34% had femoral DVT

▪ 10% had history of prior DVT; leaving 24% with new dx of DVT

▪ Independent predictors of DVT: previous hx of DVT; bedbound in past 12 wks; lower limb edema

▪ 43% of participants were on LMW heparin, DOAC or warfarin on admission to the study

▪ No mention of whether Rx was continued or not during the study

▪ Outcome: mean survival with DVT- 30.6 days mean survival without DVT- 31.4 days No difference in symptoms over 3 weeks in those with and without DVT 4 participants (2%) developed DVT over the 3 week study period

▪ TAKE HOME POINT:

▪ DVT= HIGHT PREVALENCE BUT LOW SYMPTOM BURDEN IN HOSPICE

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▪ Limitations: ▪ Study had adequate power to estimate DVT prevalence but not survival

▪ Prevalence of venous thromboembolism may be even higher in this population since study did not measure distal DVT or PE and there was a learning curve for the ultrasonographers

▪ Findings only apply to those with advanced cancer, < 3 months survival

▪ No conclusions can be drawn about secondary prevention and symptoms or survival

▪ Other Relevant Studies:

1. Tardy B, Picard S, Guirimand F, et al. Bleeding risk of terminally ill patients hospitalized in palliative care units: the RHESO study. J Thromb Haemost 2017; 15: 420–8.

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▪ Summary and Implications:

▪ This study supports the discontinuation of DVT prophylaxis in patients in the hospice setting, suggesting it does not change symptom burden and may not change survival

▪ Questions:

▪ 1. Should DVT prophylaxis/treatment be determined by setting? ▪ E.g. hospital patient receives it and hospice/ home care patient

does not ▪ Factors to consider- goals of care, prognosis, bleeding risk.

2. Are we overprescribing DVT prophylaxis in this population?

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▪ The Question:

In patients with advanced cancer with nausea and vomiting, is an approach using etiology/pathophysiology better than a single agent?

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▪ Funding: sponsored by the Palliative Care Clinical Studies Collaborative and funded by the National Health and Medical Research Council of Australia.

▪ Time Period: October 2010 to April 2014

▪ Setting: 11 sites across Australia

▪ Study Design: Randomized, prospective, open label, dose escalating trial

▪ Who was studied: patients > 18 yrs old, dx of cancer, nausea score > = 3, not on anti emetics

▪ Who was excluded: iatrogenic or reversible cause of nausea where a specific anti emetic was indicated; patients undergoing a procedure likely to affect nausea; contraindication to study medications; change in steroid dose; poor performance status (indicating unlikely to complete the study)

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▪ How many patients: 185 (sample size was calculated on the premise that a 25%

improvement over single agent therapy would be clinically relevant)

▪ Intervention: etiology based CPG treatment (first line Rx, with subsequent Rx added every 24 hours) vs. Haldol 1 mg/24 hrs, increased by 1 mg every 24 hrs to a max of 3 mg/24 hrs Oral or parenteral administration Metoclopramide 10 mg q4H prn given as rescue medication unless already on metoclopramide in which case Haldol 0.5 mg q6H prn was used

▪ Follow Up: 72 hours

▪ Primary Outcome: proportion of patients who responded to treatment at 72 hours

▪ Definition of Response: 2-point reduction in average nausea score and a score < 3 for average nausea over the preceding 24 h, measured at 72 hr.

▪ Treatment related adverse events also reported

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Guideline Based Treatment Arm

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▪ Results ▪ the majority of patients in both groups had multifactorial causes for their nausea > 2 wks

▪ greater response rate was seen in the guideline arm than the single agent arm at 24 h (49% vs 32%; p = 0.02), but not at 48 or 72 h.

▪ response rates at 72 h in the intention to treat analysis were 49 and 53% respectively, with no significant difference between arms (0·04; 95% CI:-0·11, 0·19; p = 0·59)

▪ ≥1 episode of vomiting/day decreased from 33% at baseline to 17% at 72 h in both treatment arms.

▪ few adverse events in each arm (>50% had adverse events at baseline)

▪ Patients who withdrew were classified as non responders

▪ 21% drop out rate due to clinical deterioration, unplanned intervention, treatment ineffective, revoked consent

▪ Use of rescue medication was the same in both groups at 24 and 72 hours but was higher in the single agent arm at 48 hrs (43% vs 22%, p =0.003)

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Adverse Events

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▪ Limitations: ▪ Not blinded

▪ Primary cause was only found in 54% of patients, limiting the effectiveness of etiology based guidelines (e.g. it was really just a comparison of metoclopramide/haldol vs. haldol)

▪ Short duration of observation (72 hrs), can the nausea be controlled over wks-months?

▪ Other Relevant Studies: 1. Walsh D, Davis M, Ripamonti C, et al. 2016 updated MASCC/ESMO Consensus recommendations: management of nausea and vomiting in advanced cancer. Support Care Cancer. Jan 2017.

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▪ Summary and Implications: ▪ An etiology-based, guideline-directed approach to antiemetic therapy may offer

more rapid benefit, but is no better than single agent treatment with haloperidol at 72 h.

▪ Questions: 1. Are there benefits to teaching a mechanistic/etiology approach to nausea even

if it does not lead to evidence based therapeutic benefit?

2. Do you use the guideline based approach or are you using olanzapine and ondansetron (e.g. medication not even used in this study)?

3. How important is it to control nausea at 24 vs 72 hours?

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▪ The Question:

What is the effect of psychotherapy on depression and anxiety among individuals

with any condition appropriate for palliative care?

What types of psychotherapy were most effective?

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▪ Study Design: meta analysis ▪ Eligible studies were randomized controlled trials of psychotherapy that

reported outcomes of depression and anxiety and included adults with serious illnesses.

▪ Funding: No external funding

▪ Time Period: earliest records to Aug 17, 2017

▪ Who was Studied: ▪ Adults > 18 yrs old ▪ psychotherapy that involved at least two sessions or a minimum of 60

minutes of intervention ▪ Depression and anxiety assessed as continuous variable ▪ Randomised controlled study design published in a peer reviewed journal

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▪ Who was Excluded:

▪ studies published in languages other than English

▪ Studies of psychotherapies focusing on marital functioning, physical symptom reduction (e.g., pain), or health behavior change, and those that involved only psychoeducation, single skill building (e.g., relaxation), or support were excluded.

▪ How many patients: ▪ 32 original studies with 36 samples: cancer (18); multiple sclerosis (6);

HIV (4); advanced illness (4); other (4). ▪ N= 1536

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▪ Intervention: ▪ Individual psychotherapy (23); group psychotherapy (10); family therapy

(3) ▪ Face to face (31); by phone (5) ▪ 81% administered by mental health providers ▪ Type of psychotherapy:

▪ Cognitive behavioural (21) ▪ cognitive behavioral therapy (CBT), cognitive therapy, problem solving therapy, and interpersonal

therapy ▪ Existential therapy (10) ▪ dignity, legacy, life review, and meaning making ▪ Other (5) ▪ acceptance and commitment therapy [ACT],mindfulness based stress reduction [MBSR], and

supportive expressive therapy

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▪ Follow-up: ▪ Average number of sessions was 8.96, follow up time was not specified

▪ End Points: ▪ standardized mean gain score in depression and anxiety (i.e., standardized

change in scores from pre-treatment to post-treatment) computed as a measure of effect size

▪ Mean effect size calculated and homogeneity analysis performed

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Forest Plot of Depression

Effect Size

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Forest Plot of Anxiety

Effect Size

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▪ Results ▪ Psychotherapy in palliative populations had a significant effect on depression and

anxiety symptoms

▪ Psychotherapy had a large effect on depression and a small effect on anxiety

▪ Psychotherapy results I a small but significant improvement in QoL

▪ Cognitive and other therapies had a greater effect on depression than existential therapies

▪ Mental health providers delivering the therapy had a greater effect on depression than health care providers

▪ Effect size was smaller for older patients

▪ Effect size was smaller for longer individual sessions (e.g. sessions should be <75 min for palliative patients)

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▪ Limitations: ▪ This meta analysis did not address the duration of effect of psychotherapy

▪ Publication bias may have been present in the studies on depression

▪ Most of the studies involved patients with cancer

▪ The CALM RCT was not included

▪ Other Relevant Studies: 1. Gary Rodin, Christopher Lo, Anne Rydall et al. Managing Cancer and Living Meaningfully (CALM): A Randomized Controlled Trial of a Psychological Intervention for Patients With Advanced Cancer. J Clin Oncol 36:2422-2432. 2018

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▪ Summary and Implications: ▪ Psychotherapy (at least 2 sessions) has a large effect on symptoms of depression

and small effect on symptoms of anxiety in a palliative population

▪ This suggests that mental health professionals should be a part of palliative care teams

▪ Questions: 1. How does psychotherapy compare to antidepressant therapy in this population?

2. Does your service have trained mental health providers? If not, do you think these interventions can be delivered effectively by MDs, or nurses? How much training is required?

3. What do we do with patients who we identify as needing psychotherapy but they are not interested? Can we deliver effective psychotherapy while we deliver clinical care?

4. Given the variety of psychotherapy interventions and limited resources, how do we choose the ones to deliver?

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References

1. Rosian K, Hawlik K, Piso B. Efficacy assessment of radiofrequency ablation as a palliative pain treatment in patients with painful metastatic spinal lesions: a systematic review. Pain Physician 2018;21:E467-E476.

2. Berenson J, Pflugmacher R, Jarzem P et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicenter, randomized controlled trial. Lancet Oncol 2011;12:225-35.

3. Bhatnagar R, Keenan EK, Morley AJ et al. Outpatient talc administration by indwelling pleural catheter for malignant effusion. N Engl J Med 2018;378:1313-22.

4. Thomas R, Fysh ETH, Smith NA et al. Effect of an indwelling pleural catheter vs talc pleurodesis on hospitalization days in patients with malignant pleural effusion: the AMPLE randomized clinical trial. JAMA 2017;318(19):1903-1912. doi:10.1001/jama.2017.17426

5. White C, Noble SIR, Watson M et al. Prevalence, symptom burden, and natural history of deep vein thrombosis in people with advanced cancer in specialist palliative care units (HIDDen): a prospective longitudinal observational study. Lancet Haematol 2019;6:e79-88.

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References

1. Tardy B, Picard S, Guirimand F, et al. Bleeding risk of terminally ill patients hospitalized in palliative care units: the RHESO study. J Thromb Haemost 2017; 15: 420–8.

2. Hardy J, Skerman H, Glare P, et al. A randomized open-label study of guideline-driven antiemetic therapy versus single agent antiemetic therapy in patients with advanced cancer and nausea not related to anticancer treatment. BMC Cancer. 2018;18(1):510.

3. Walsh D, Davis M, Ripamonti C, et al. 2016 updated MASCC/ESMO Consensus recommendations: management of nausea and vomiting in advanced cancer. Support Care Cancer. Jan 2017. 25(1):333-340.

4. Fulton J, Newins A, Porter L, et al. Psychotherapy Targeting Depression and Anxiety for use in Palliative Care: A Meta- Analysis. Journal of Palliative Medicine. Jul 2018.

5. Rodin G, Lo C, Rydall A, et al. Managing Cancer and Living Meaningfully (CALM): A Randomized Controlled Trial of a Psychological Intervention for Patients With Advanced Cancer. J Clin Oncol 36:2422-2432. 2018

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