Abstract
Background: Phase 1 clinical trials remain vital for oncology care. Patients on these trials require supportive care for quality-of-life (QOL) concerns.
Objective: To test a Palliative Care Intervention (PCI) for patients with solid tumors enrolled in Phase I therapeutic trials with a priori hypothesis that psychological distress, QOL, satisfaction, symptoms, and resource utilization would be improved in the PCI group.
Design: This unblinded randomized trial compared the PCI with usual care in patients accrued to Phase I Clinical Trials. Subjects (n = 479) were followed for 24 weeks, with 12 weeks as the primary outcome.
Setting: Two Comprehensive Cancer Centers in the United States.
Subjects: A consecutive sample, 21 years or older, English fluency, with solid tumors initiating a Phase 1 trial. Measurements: Psychological Distress (Distress Thermometer), QOL total and subscales (FACT-G), satisfaction (FAM-CARE), survival, and resource utilization (chart audit).
Results: PCI subjects showed improved Psychological Distress (−0.47, p = 0.015) and Emotional Well-Being (0.81, p = 0.045), with differences on variables of QOL and distress between sites. High rates of symptom-management admissions (41.3%) and low rates of Advance Directive completion (39.0%), and hospice enrollment (30.7%), despite a median survival in both groups of 10.1 months from initiating a Phase 1 study.
Conclusions: A nurse-delivered PCI can improve some QOL outcomes and distress for patients participating in Phase 1 trials. Greater integration of PC is needed to provide quality care to these patients and to support transitions from treatment to supportive care, especially at the end of life.
ClinicalTrials.gov Identifier: NCT01612598.
Keywords: palliative care, palliative care intervention, phase 1 clinical trials, quality of life
Introduction
Patients and families participating in Phase I trials can be especially vulnerable and, therefore, may need special attention.1–4 Palliative care (PC) has helped in serious illness with better communication, symptom control, knowledge about treatment options and goals, and improved survival.5–10 Phase I patients are generally among the most “well” of advanced cancer patients, but even so, in one study they had a symptom burden similar to other oncology patients.11 In another study, after measuring patient status by using the Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores, Phase I patients were more likely to have 5 of 10 serious symptoms and greater severity for 6 of 10 symptoms.8 In a preliminary study of the first 178 patients enrolled in the trial reported here, there was a significant symptom burden,12 with emotional distress predominant.13 The population of patients in Phase 1 trials has advanced disease, often unrealistic hope for cure, and receives no PC or late referral to these services.14–17 Despite the illness's terminal nature and average survival of just several months, oncologists rarely discuss prognosis during Phase I trial discussions.1–3 A study of Phase I patients verified that nearly half of the patients had some advance care planning, and 59% wanted to discuss this with their health care providers.18
In addition to a baseline symptom burden, a patient's symptomology while on a Phase I trial may increase during participation. The drugs and trials may have substantial toxicities, including side effects, requiring multiple clinic visits, time from family, and caregiver distress. Finally, patients often have worsening performance status and increasing symptoms as their cancer progresses.19–24
We previously tested a palliative care intervention (PCI) delivered by nurses who recruited and consented patients and caregivers, did baseline PC assessments, worked with an interdisciplinary team (IDT) to create a care plan, and did two teaching sessions with a standardized workbook.25 In this study, we applied the PCI to a new population of Phase I patients.
Materials and Methods
Aims
This study's primary purpose was to test a PCI for patients with solid tumors undergoing Phase I therapeutic clinical trials in a randomized, two-center study. The study's aims were to compare the intervention versus control groups to: (1) test the effects of a PCI on patients' quality of life (QOL), psychological distress, and satisfaction with oncology care and communication; (2) test the effects of a PCI on patients' symptoms, comparing the intervention versus control groups; (3) test the effects of a PCI on patients' hospital and PC resource utilization, comparing the intervention versus control groups; (4) test the effects of a PCI on overall survival; and (5) describe patients' satisfaction with the PCI.
Study design
The unblinded, randomized parallel assignment trial compared two groups of patients accrued just before initiating a Phase 1 Clinical Trial. The two trial groups were (1) Usual Care (UC) and (2) a PCI, described next. Two NCI-designated comprehensive cancer centers participated, with site 1 on the west coast and site 2 on the east coast of the United States. The trial was approved by Institutional Review Boards at each site and registered with ClinicalTrials.gov ID NCT01612598.
Participants
Inclusion criteria were 21 years of age or older, English fluency, no cognitive impairment, diagnosed with a solid tumor, and initiating Phase 1 Clinical Trial participation. Figure 1 presents the Consort Diagram for the participants. Patients were accrued to this study and completed written informed consent, after consenting to the Phase 1 trial, with baseline data required to be collected before the first dose.
FIG. 1.
Consort Diagram.
Randomization
A randomized variable block design (with block size 4, 6, or 8) was used to generate the randomization lists a priori, and it was stratified by the accruing institution. Randomization assignment (PCI vs. Control arm) was determined on informed consent for each patient, and it was revealed to the research nurse at that time. After the 12-week evaluation, control group patients were given the opportunity to cross to the PCI arm to receive the intervention. For this reason, we did not use time points past 12 weeks for comparisons between groups. (Consort Diagram Fig. 1)
Trial conditions and procedures
Patients assigned to the UC group received standard care for patients enrolled in a Phase 1 trial by their medical oncologist and clinical trial nurses. Procedures for patients in the PCI group included: (1) a care plan created by the study nurse based on data from the baseline evaluation, including QOL measures and symptoms described next; (2) a discussion of the patient in an interdisciplinary meeting of the study investigators, nurses, a chaplain, and social worker. When possible, the patient's oncologist was invited to participate in the discussion. If the oncologist could not participate, suggestions were communicated to the oncologist, as indicated; (3) the discussion included an assessment of the patient's understanding of the goals of care; (4) the patient received two teaching sessions by the research nurse using standardized teaching materials addressing symptom and QOL concerns. These aspects of the intervention were completed within four weeks of baseline.
The study was performed at two Comprehensive Cancer Centers with robust Phase I programs. At both sites, the treating oncologist retained responsibility for the patient, working with the Phase I clinical trials team. This also was not a standard PC consultation service visit as done in other trials, with monthly visits to an advance practice nurse or physician. The PC consultation could be requested by the physicians in either arm. The content was organized by QOL domains, including physical, psychological, social, and spiritual well-being.
Outcome measures
A demographic data tool, chart audit tool, patient satisfaction with the intervention tool, as well as three standard psychosocial measures were included in the study. In addition, the Patient Reported Outcome version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) symptom tool and Functional Assessment of Chronic Illness Therapy–Spiritual Well-being 12 (FACIT-Sp-12) spirituality tool were used and are reported separately. The standard measures were:
Demographic data tool
This tool documented race, ethnicity, gender, age, and other descriptive variables. These variables were recorded by the participant in categories listed on the tool.
Psychological distress scale
The Distress Thermometer is a single item asking patients to rate their distress on a scale of 0 (no distress) to 10 (extreme distress).26
Functional assessment of cancer therapy–general
The Functional Assessment of Cancer Therapy–General (FACT-G)30 is a well-established QOL scale in oncology consisting of 27 items rated on a 0 = Not at all to 4 = Very much scale. Negatively stated items are reversed in the scoring process. Higher scores indicate better QOL. The tool includes subscales of Physical, Social, Emotional Well-Being (EWB), and Functional Well-Being (FWB), which are tallied to achieve a total score indicating overall QOL.27
FAMCARE-P13
This family satisfaction with cancer care tool measures aspects of family caregiver satisfaction with their oncology care and communication, with the scale ranging from 0 = Very Dissatisfied to 4 = Very Satisfied.28,29 Thirteen items assess aspects of satisfaction with symptom assessment, pain management, and receiving information about tests and prognosis. Higher scores indicate greater satisfaction.
Statistical analysis
This study was designed as a randomized, prospective, longitudinal two-group experiment, powered to detect significant group differences in psychological distress, symptom intensity, and symptom severity; however, QOL and related metrics were included as secondary endpoints. We determined that a sample size of 336 patients would be sufficient to detect an effect size of 0.25 or greater, with at least 90% power, in the primary outcome measures defined (distress, and symptom intensity/interference). Accrual goals were set at 480, to account for 30% attrition at 12 weeks. The study accrued 479 patients with baseline data available.
SAS 9.4® was used to conduct analyses. Data were analyzed according to the intent to treat. Descriptive statistics were generated for all data collected, instrument scores were calculated according to instructions, and distributions were examined. Baseline data for the FACT-G and Psychological Distress tools were used to estimate reliability for this study's subjects for this instrument. Fisher's exact test was used for comparing categorical data between enrollment sites when appropriate. Kaplan–Meier (KM) method was used to calculate survival estimates and 95% confidence intervals and to generate overall survival curves, and the reverse-KM method was used for calculation of median follow-up.
Mixed model with repeated measures (MMRM)—with three time points: baseline, 4 weeks, and 12 weeks—was used for prediction of outcome measures, and to determine significance of effects from treatment arm as well as interaction effects between treatment arm, evaluation time point, and enrolling institution. Week 24 data were not used in these analyses, as the control group was offered participation in the PCI program after week 12. The main effects of demographic variables were also studied, along with interaction of these variables with evaluation of time points and study intervention, within the setting of the mixed model. Gender, race, education level, marital status, family income, employment status, and enrolling institution were the variables tested. Patients who received at least part of the intervention were included in the MMRM analysis (n = 427).
Differences in least-squares means estimates between baseline and 12 weeks were used to calculate change in the overall FACT-G Index and subscale scores, Psychological Distress, and the FAMCARE Communication score. Statistical significance was determined with t-tests, using Tukey–Kramer adjustments in pairwise comparisons of least-square means across subgroups in MMRM. A type I error of 0.05 was used as a threshold for statistical significance. Patients were included in the MMRM analysis if they had at least baseline and either Week 4 or Week 12 metrics collected.
Results
Demographic data
Table 1 summarizes patient demographics, with stratification by enrolling institution and study arm. The median age was 62. Patients were mostly female (56.8%) and Caucasian (69.3%). The median number of comorbidities from chart review and patient interview was 1 (IQR: 1–3), with a majority of patients reporting 1 (25.9%), 2 (22.8%), or 3 (15.9%) comorbidities.
Table 1.
Baseline Characteristics By Enrolling Institution and Study Arm
| All patients (n = 479) | PC intervention (n = 240) | Control (n = 239) | Site 1 (n = 291) | Site 2 (n = 188) | |
|---|---|---|---|---|---|
| Age, median (IQR) | 62 (53–69) | 62 (54–69) | 62 (53–69) | 62 (54–69) | 62 (53.5–69) |
| <50 | 85 (17.8%) | 41 (17.1%) | 44 (18.4%) | 51 (17.5%) | 32 (18.1%) |
| 50–59 | 128 (16.7%) | 66 (27.5%) | 62 (26.0%) | 78 (16.8%) | 50 (26.6%) |
| 60–69 | 160 (33.4%) | 78 (33.5%) | 82 (34.3%) | 93 (32.0%) | 77 (35.7%) |
| 70–79 | 93 (19.4%) | 48 (20.0%) | 55 (18.8%) | 60 (20.6%) | 32 (17.6%) |
| 80+ | 13 (2.7%) | 7 (2.9%) | 6 (2.5%) | 9 (3.1%) | 4 (2.1%) |
| Gender, N (%) | |||||
| Female | 272 (56.8%) | 133 (55.4%) | 139 (58.2%) | 165 (56.7%) | 107 (56.9%) |
| Male | 207 (43.2%) | 107 (44.6%) | 100 (41.8%) | 126 (43.3%) | 81 (43.1%) |
| Race/ethnicity, N (%) | |||||
| African American | 34 (7.1%) | 21 (8.8%) | 13 (5.4%) | 11 (3.8%) | 23 (12.2%) |
| Asian | 46 (9.6%) | 22 (9.2%) | 24 (10.0%) | 43 (14.8%) | 3 (1.6%) |
| Caucasian | 332 (69.3%) | 165 (68.8%) | 167 (69.9%) | 181 (62.2%) | 151 (80.3%) |
| Hispanic Latino | 43 (9.0%) | 21 (8.8%) | 22 (9.2%) | 41 (14.1%) | 2 (1.1%) |
| Native Hawaiian | 6 (1.3%) | 3 (1.3%) | 3 (1.3%) | 5 (1.7%) | 1 (0.5%) |
| Mixed race | 12 (2.5%) | 5 (2.1%) | 7 (2.9%) | 8 (2.7%) | 4 (2.1%) |
| Other | 6 (1.3%) | 3 (1.3%) | 3 (1.3%) | 2 (0.7%) | 4 (2.1%) |
| Education, N (%) | |||||
| Did not complete high school | 7 (1.5%) | 4 (1.7%) | 3 (1.3%) | 3 (1.0%) | 4 (2.1%) |
| High school | 109 (22.8%) | 47 (19.6%) | 62 (25.9%) | 53 (18.2%) | 56 (29.8%) |
| College | 258 (53.9%) | 131 (54.6%) | 127 (53.1%) | 195 (67.0%) | 63 (33.5%) |
| Graduate/professional school | 96 (20.0%) | 54 (22.5%) | 42 (17.6%) | 31 (10.7%) | 65 (34.6%) |
| No response | 9 (1.9%) | 4 (1.7%) | 5 (2.2%) | 9 (3.1%) | 0 (0.0%) |
| Religion, N (%) | |||||
| None | 79 (16.5%) | 37 (15.4%) | 42 (17.6%) | 58 (19.9%) | 21 (11.2%) |
| Protestant | 186 (38.8%) | 103 (42.9%) | 83 (34.7%) | 103 (35.4%) | 83 (44.1%) |
| Catholic | 141 (29.4%) | 66 (27.5%) | 75 (31.4%) | 92 (31.6%) | 49 (26.1%) |
| Jewish | 28 (5.8%) | 13 (5.4%) | 15 (6.3%) | 18 (6.2%) | 10 (5.3%) |
| Other | 43 (9.0%) | 19 (7.9%) | 24 (10.0%) | 20 (6.9%) | 23 (12.2%) |
| No response | 2 (0.4%) | 2 (0.8%) | 0 (0.0%) | 0 (0.0%) | 2 (1.1%) |
| Marital status, N (%) | |||||
| Never married | 21 (4.4%) | 11 (4.6%) | 10 (4.2%) | 15 (5.2%) | 6 (3.2%) |
| Married/living with partner | 359 (74.9%) | 180 (75.1%) | 179 (74.9%) | 209 (71.8%) | 150 (79.8%) |
| Divorced/separated | 64 (13.3%) | 30 (12.7%) | 34 (14.2%) | 44 (15.1%) | 20 (11.7%) |
| Widowed | 32 (6.7%) | 17 (7.1%) | 15 (6.3%) | 21 (7.2%) | 11 (5.9%) |
| No response | 3 (0.6%) | 2 (0.8%) | 1 (0.4%) | 3 (1.0%) | 0 (0.0%) |
| Other members in household, N (%) | |||||
| None (lives alone) | 59 (12.3%) | 30 (12.5%) | 29 (12.1%) | 39 (13.4%) | 20 (10.6%) |
| Spouse | 213 (44.5%) | 105 (43.8%) | 108 (45.2%) | 126 (43.3%) | 87 (46.3%) |
| Children | 25 (5.2%) | 12 (5.0%) | 13 (5.4%) | 18 (6.2%) | 7 (3.7%) |
| Friend | 22 (4.6%) | 12 (5.0%) | 10 (4.2%) | 16 (5.5%) | 6 (3.2%) |
| Multiple relatives/friends | 157 (32.8%) | 80 (33.3%) | 77 (32.2%) | 89 (30.6%) | 68 (36.2%) |
| No response | 3 (0.6%) | 1 (0.4%) | 2 (0.8%) | 3 (1.0%) | 0 (0.0%) |
| Employment status, N (%) | |||||
| Employed full time | 114 (23.8%) | 59 (24.6%) | 55 (23.0%) | 54 (18.6%) | 60 (31.9%) |
| Employed part time | 54 (11.3%) | 31 (12.9%) | 23 (9.6%) | 39 (13.4%) | 15 (8.0%) |
| Homemaker | 33 (6.9%) | 15 (6.3%) | 18 (7.5%) | 17 (5.8%) | 16 (8.5%) |
| Retired | 191 (39.9%) | 91 (37.9%) | 100 (41.8%) | 115 (39.5%) | 76 (40.4%) |
| Student | 1 (0.2%) | 0 (0.0%) | 1 (0.4%) | 1 (0.3%) | 0 (0.0%) |
| Unemployed | 79 (16.5%) | 42 (17.5%) | 37 (15.5%) | 61 (21.0%) | 18 (9.6%) |
| No response | 7 (1.5%) | 2 (0.8%) | 5 (2.1%) | 4 (1.4%) | 3 (1.6%) |
| Family income, N (%) | |||||
| $10,000 or less | 7 (1.5%) | 4 (1.7%) | 3 (1.3%) | 0 (0.0%) | 7 (3.7%) |
| $10,001 to $20,000 | 10 (2.1%) | 4 (1.7%) | 6 (2.5%) | 1 (0.3%) | 9 (4.8%) |
| $20,001 to $30,000 | 17 (3.5%) | 10 (4.2%) | 7 (2.9%) | 10 (3.4%) | 7 (3.7%) |
| $30,001 to $40,000 | 27 (5.6%) | 12 (5.0%) | 15 (6.3%) | 17 (5.8%) | 10 (5.3%) |
| $40,001 to $50,000 | 98 (20.5%) | 48 (20.0%) | 50 (20.9%) | 81 (27.8%) | 17 (9.0%) |
| Greater than $50,000 | 289 (60.3%) | 144 (60.0%) | 145 (60.7%) | 159 (54.6%) | 130 (69.1%) |
| No response | 31 (6.5%) | 18 (7.5%) | 13 (5.4%) | 23 (7.9%) | 8 (4.3%) |
| Type of cancer, N (%) | |||||
| Bladder | 13 (2.7%) | 6 (2.5%) | 7 (2.9%) | 13 (4.5%) | 0 (0.0%) |
| Breast | 38 (7.9%) | 18 (7.5%) | 20 (8.4%) | 25 (8.6%) | 13 (6.9%) |
| Cervical | 9 (1.9%) | 5 (2.1%) | 4 (1.7%) | 5 (1.7%) | 4 (2.1%) |
| Colon | 80 (16.7%) | 42 (17.5%) | 38 (15.9%) | 45 (15.5%) | 35 (18.6%) |
| Lung | 73 (15.2%) | 34 (14.2%) | 39 (16.3%) | 54 (18.6%) | 19 (10.1%) |
| Ovarian | 42 (8.8%) | 16 (6.7%) | 26 (10.9%) | 29 (10.0%) | 13 (6.9%) |
| Pancreatic | 42 (8.8%) | 26 (10.8%) | 16 (6.7%) | 18 (6.2%) | 24 (12.8%) |
| Prostate | 21 (4.4%) | 9 (3.8%) | 12 (5.0%) | 12 (4.1%) | 9 (4.8%) |
| Rectal | 28 (5.8%) | 14 (5.8%) | 14 (5.9%) | 17 (5.8%) | 11 (5.9%) |
| Other | 133 (27.8%) | 70 (29.2%) | 63 (26.4%) | 73 (25.1%) | 60 (31.9%) |
| Current and previous surgical procedure, N (%) | |||||
| Yes | 345 (72.0%) | 172 (71.7%) | 173 (72.4%) | 214 (73.5%) | 131 (69.7%) |
| No | 127 (26.5%) | 64 (26.7%) | 63 (26.4%) | 76 (26.1%) | 51 (27.1%) |
| No response | 7 (1.5%) | 4 (1.7%) | 3 (1.3%) | 1 (0.3%) | 6 (3.2%) |
| Current and previous chemotherapy, N (%) | |||||
| Yes | 422 (88.1%) | 202 (84.2%) | 220 (92.1%) | 254 (87.3%) | 168 (89.4%) |
| No | 51 (10.6%) | 34 (14.2%) | 17 (7.1%) | 34 (11.7%) | 17 (9.0%) |
| No response | 6 (1.3%) | 4 (1.7%) | 2 (0.8%) | 3 (1.0%) | 3 (1.6%) |
| Current and previous radiation therapy, N (%) | |||||
| Yes | 212 (44.3%) | 104 (43.3%) | 108 (45.2%) | 132 (45.4%) | 80 (42.6%) |
| No | 249 (52.0%) | 124 (51.7%) | 125 (52.3%) | 154 (52.9%) | 95 (50.5%) |
| No response | 18 (3.8%) | 12 (5.0%) | 6 (2.5%) | 5 (1.7%) | 13 (6.9%) |
| Tried alternative therapies, N (%) | |||||
| Yes | 120 (25.1%) | 62 (25.8%) | 58 (24.3%) | 72 (24.7%) | 48 (25.5%) |
| No | 343 (71.6%) | 169 (70.4%) | 174 (72.8%) | 206 (70.8%) | 137 (72.9%) |
| No response | 16 (3.3%) | 9 (3.8%) | 7 (2.9%) | 13 (4.5%) | 3 (1.6%) |
| Number of comorbidities, median (IQR) | 1 (1–3) | 2 (1–3) | 1 (0–3) | 2 (1–3) | 1 (0–2) |
| 0 | 118 (24.6%) | 56 (23.3%) | 62 (25.9%) | 53 (18.2%) | 65 (22.6%) |
| 1 | 124 (25.9%) | 59 (24.6%) | 65 (27.2%) | 68 (23.4%) | 56 (19.4%) |
| 2 | 109 (22.8%) | 59 (24.6%) | 50 (20.9%) | 74 (25.4%) | 35 (12.2%) |
| 3 | 76 (15.9%) | 36 (15.0%) | 40 (16.7%) | 54 (18.6%) | 22 (7.6%) |
| 4 | 34 (7.1%) | 20 (8.3%) | 14 (5.9%) | 38 (13.1%) | 6 (2.1%) |
| ≥5 | 18 (3.8%) | 10 (4.2%) | 8 (3.3%) | 14 (4.8%) | 4 (1.4%) |
Effect of intervention
To study the PCI effect, change in the overall FACT-G Index and subscale scores, Psychological Distress, and FAMCARE Communication scores were studied by using MMRM, examining the effects of time, treatment arm, enrolling institution, and interaction of these variables. Table 2 summarizes the differences of least-square means from baseline to Week 12 for (1) all patients combined, (2) intervention patients only, and (3) control patients only. Results are further stratified by enrolling site to help understand the effect of the intervention within each enrolling institution. Further, we include the comparison between (4) the intervention and control group, which provides results for the effectiveness of the intervention with respect to the control group across all time points (Aim 1).
Table 2.
Mixed Model with Repeated-Measures Differences of Least-Squares Means (SE) in Distress, Quality of Life, and FamCare, from Baseline to Week 12
| Instrument/subscales | Accruing institution | (1) All subjects combined BL to W12 | (2) Interv BL to W12 | (3) Control BL to W12 | (4) Interv vs. Cntl† |
|---|---|---|---|---|---|
| FACT-G index (QOL) | Both sites | 0.66 (0.58) | 0.98 (0.83) | 0.34 (0.81) | 1.58 (1.31) |
| Site 1 | 5.02 (0.65)** | 6.99 (0.91)** | 3.04 (0.93) | 5.27 (1.56)** | |
| Site 2 | −3.70 (0.96)** | −5.02 (1.39)* | −2.37 (1.33) | −2.11 (2.12) | |
| PWB | Both sites | −1.02 (0.23)** | −0.83 (0.33) | −1.21 (0.32)** | 0.06 (0.44) |
| Site 1 | −0.30 (0.26) | 0.27 (0.36) | −0.86 (0.37) | 1.00 (0.52) | |
| Site 2 | −1.74 (0.38)** | −1.93 (0.55)* | −1.55 (0.53) | −0.88 (0.71) | |
| SWB | Both sites | 0.07 (0.16) | 0.04 (0.22) | 0.11 (0.22) | 0.20 (0.39) |
| Site 1 | 0.57 (0.18)* | 0.78 (0.24) | 0.36 (0.25) | 0.68 (0.46) | |
| Site 2 | −0.42 (0.26) | −0.70 (0.37) | −0.14 (0.36) | −0.28 (0.62) | |
| EWB | Both sites | 1.47 (0.22)** | 1.60 (0.31)** | 1.34 (0.31)** | 0.81 (0.40)* |
| Site 1 | 2.97 (0.25)** | 3.55 (0.34)** | 2.39 (0.35)** | 1.87 (0.47)** | |
| Site 2 | −0.03 (0.36) | −0.36 (0.52) | 0.29 (0.50) | −0.25 (0.65) | |
| FWB | Both sites | 0.23 (0.23) | 0.23 (0.33) | 0.22 (0.32) | 0.49 (0.48) |
| Site 1 | 1.84 (0.26)** | 2.44 (0.36)** | 1.24 (0.37)* | 1.72 (0.57)* | |
| Site 2 | −1.38 (0.38)** | −1.97 (0.55)* | −0.79 (0.53) | −0.74 (0.78) | |
| FC | Both sites | 0.81 (0.34)* | 0.88 (0.49) | 0.74 (0.47) | 1.01 (0.53) |
| Site 1 | 0.34 (0.37) | 0.33 (0.52) | 0.35 (0.54) | 0.77 (0.63) | |
| Site 2 | 1.28 (0.56) | 1.42 (0.82) | 1.14 (0.76) | 1.24 (0.86) | |
| Distress | Both sites | −1.15 (0.12)** | −1.43 (0.18)** | −0.87 (0.17)** | −0.47 (0.19)* |
| Site 1 | −2.03 (0.14)** | −2.37 (0.19)** | −1.69 (0.20)** | −0.93 (0.22)** | |
| Site 2 | −0.26 (0.21) | −0.48 (0.30) | −0.04 (0.28) | −0.01 (0.31) |
Interv versus Cntl column: demonstrates effect of PCI versus control group over time.
Statistically significant results from t-test with Tukey–Kramer adjustment are denoted with *(p < 0.05).
(p < 0.01).
Interv, intervention; Cntl, control; PWB, physical well-being; SWB, social well-being; EWB, emotional well-being; FWB, functional well-being; FC, FAMCARE communication tool; Distress, psychological distress.
The effect of PCI versus control was significant in two main areas studied. We observed a larger reduction in PCI versus control patients in psychological distress (−0.47, p = 0.015), and more improved Emotional Well-Being (EWB) subscale scores (0.81, p = 0.045). The differences were more pronounced within site 1, where the overall reduction in distress was larger (−0.93, p = 0.0003), and improvement in EWB was greater (1.87, p = 0.0006) in PCI patients versus control, over time. We further saw an increase in overall FACT-G/QOL scores within site 1 (5.27, p = 0.0044), which is not seen at site 2. FC (family communication) scores were not significantly changed in either PCI or control groups, but a nominal change was seen from Baseline (BL) to W12 in both groups combined (0.81, p = 0.045).
Both PCI and control patients were noted to have significant improvements in psychological distress, as there was an average 1.15-point decrease (on 10-point scale) in both groups combined, and a 2.03-point decrease within site 1 (p < 0.0001 for both). Other results indicated improvements in overall FACT-G scores in site 1 (5.02, p < 0.0001) from BL to W12, but a decrease in the same scale within site 2 (−3.70, p < 0.0018). Change in EWB scores was also slightly different within the two sites, with a 1.47- versus 2.97-point increase seen from BL to W12 at site 1 and site 2, respectively. Thus, the effect of the intervention was not consistent across enrolling institution. Figure 2 displays the most significant and relevant results in the study.
FIG. 2.
Change in Scores from Baseline to Week 12.
Aim 2 was evaluated by focus on the Physical subscale (PWB) of the FACT-G, which measures 7 physical symptoms; NCI (National Cancer Institute) PRO-CTCAE data will be reported separately.
Resource utilization
Table 3 summarizes data collected for Aim 3 regarding resource utilization and treatments from the medical record at the conclusion of the subject's participation in the study with a further breakdown of data by enrolling institution.
Table 3.
Palliative Care Resource Utilization and Treatments
| Chart audit data elements | Both sites (n = 479) | Intervention (n = 240) | Control (n = 239) | Site 1 (n = 291) | Site 2 (n = 188) |
|---|---|---|---|---|---|
| Prior disease treatments | |||||
| Chemotherapy | 465 (97.1%) | 231 (96.3%) | 234 (97.9%) | 287 (98.6%) | 178 (94.7%) |
| Surgery | 338 (70.6%) | 165 (68.8%) | 173 (72.4%) | 204 (70.1%) | 134 (71.3%) |
| Radiation | 210 (43.8%) | 113 (47.1%) | 97 (40.6%) | 130 (44.0%) | 80 (42.6%) |
| Advance care directive (completed) | 187 (39.0%) | 98 (40.8%) | 89 (37.2%) | 125 (43.0%) | 62 (33.0%) |
| Proxy decision maker, N (%) | 168 (35.1%) | 86 (35.8%) | 82 (34.3%) | 137 (47.1%) | 31 (16.5%) |
| Code status, N (%) | |||||
| DNR | 168 (35.1%) | 90 (37.5%) | 78 (32.6%) | 134 (46.0%) | 34 (18.1%) |
| Full code | 301 (64.9%) | 150 (62.5%) | 161 (67.4%) | 157 (54.0%) | 154 (81.9%) |
| Hospice use | |||||
| Hospice referral, N (%) | 187 (39.0%) | 98 (40.8%) | 89 (37.2%) | 92 (31.6%) | 95 (50.5%) |
| Hospice enrollment, N (%) | 147 (30.7%) | 79 (32.9%) | 68 (28.5%) | 63 (21.6%) | 84 (44.7%) |
| Months from hospice referral to death, median (IQR)* | 0.7 (0.3, 1.5) | 0.6 (0.2, 1.4) | 0.9 (0.4, 1.7) | 0.6 (0.3, 1.3) | 0.9 (0.3, 1.9) |
| Months from hospice enrollment to death, median (IQR)* | 0.5 (0.2, 1.2) | 0.4 (0.1, 1.2) | 0.6 (0.3, 1.2) | 0.5 (0.2, 1.1) | 0.5 (0.20, 1.3) |
| Survival data | |||||
| Months from DNR signed to death, median (IQR)* | 5.0 (1.1, 11.0) | 3.5 (0.9, 10.7) | 6.4 (1.4, 11.0) | 8.8 (3.4, 15.7) | 1.4 (0.2, 3.8) |
| Median overall survival years from diagnosis, (95% CI) | 3 (3–4) | 3 (3–4) | 3 (3–4) | 3 (3–4) | 3 (3–4) |
| Median follow-up months (95% CI) | 26.5 (20.8–28.6) | 24.8 (19.0–28.6) | 27.4 (19.6–32.2) | 19.4 (15.7–27.25) | 32.2 (27.4–36.4) |
| Median survival months from on-study date (95% CI) | 10.1 (8.4–11.9) | 9.9 (7.6–11.7) | 10.2 (15.1–11.2) | 11.3 (8.7–13.5) | 8.3 (6.3–10.8) |
| Place of death* | |||||
| Home | 87 (26.8%) | 50 (29.8%) | 37 (23.6%) | 12 (6.6%) | 75 (52.8%) |
| Hospital | 31 (9.5%) | 13 (7.8%) | 18 (11.5%) | 13 (7.1%) | 18 (12.7%) |
| Inpatient hospice | 20 (6.2%) | 13 (7.8%) | 7 (4.5%) | 1 (0.6%) | 19 (13.4%) |
| Unknown | 187 (57.5%) | 92 (54.8%) | 95 (60.5%) | 157 (85.8%) | 30 (21.1%) |
| Referrals | |||||
| Palliative care referral, N (%) | 79 (16.5%) | 46 (19.2%) | 33 (13.8%) | 56 (19.2%) | 23 (12.2%) |
| Social work referral, N (%) | 222 (46.3%) | 113 (47.1%) | 109 (45.6%) | 182 (62.5%) | 40 (21.3%) |
Deceased patients only.
Despite being a population often with advanced disease at the point of Phase I trial participation and with multiple prior treatments, only 39.0% had an Advance Care Directive (AD) or designated proxy decision maker (35.1%) in their medical record; 64.9% retained Full Code Status. For those with Do Not Resuscitate (DNR) status who died, the time from signing a DNR to death was a median of five months. PC use was low at both sites, 16.5% combined, 19.2% site 1, and 12.2% site 2. Social work referrals were also low: 46.3% combined, 62.5% at site 1, and 21.3% at site 2.
Table 4 summarizes hospital admissions for patients while on study. There were 184 patients with a hospital admission, the majority (82.6%) of whom were unscheduled admissions and 41.3% of whom were related to uncontrolled symptoms. These patients were generally discharged home (71.1%), with only 16.8% receiving home care services. At discharge from a hospitalization, 32.1% had documented DNR status.
Table 4.
Hospital Admissions
| Both sites (n = 184) | Intervention (n = 101) | Control (n = 83) | Site 1 (n = 79) | Site 2 (n = 105) | |
|---|---|---|---|---|---|
| Type of admission, N (%) | |||||
| Scheduled | 17 (9.2%) | 7 (6.9%) | 10 (12.0%) | 11 (13.9%) | 6 (5.7%) |
| Unscheduled | 152 (82.6%) | 88 (87.1%) | 64 (77.1%) | 68 (86.1%) | 84 (80.0%) |
| Admission due to symptoms, N (%) | |||||
| Yes | 76 (41.3%) | 7 (6.9%) | 10 (12.0%) | 31 (39.2%) | 45 (42.9%) |
| No | 108 (58.7%) | 88 (87.1%) | 64 (77.1%) | 48 (60.8%) | 60 (57.1%) |
| Discharge disposition, N (%) | |||||
| Home-home care assistance (paid) | 31 (16.8%) | 25 (24.8%) | 6 (7.2%) | 11 (13.9%) | 20 (19.0%) |
| Home-no paid assistance | 100 (54.3%) | 48 (47.5%) | 52 (62.7%) | 53 (67.1%) | 47 (44.8%) |
| In-hospital death | 15 (8.2%) | 6 (5.9%) | 9 (10.8%) | 8 (10.1%) | 7 (6.7%) |
| Inpatient facility | 7 (3.8%) | 6 (5.9%) | 1 (1.2%) | 2 (2.5%) | 5 (4.8%) |
| SNF/Rehab/nursing home | 3 (1.6%) | 3 (3.0%) | 0 (0.0%) | 0 (0.0%) | 3 (2.9%) |
| Other | 9 (4.9%) | 5 (5.0%) | 4 (4.8%) | 3 (3.8%) | 6 (5.7%) |
| Code status at discharge N (%) | |||||
| Full code | 68 (36.9%) | 39 (38.6%) | 29 (34.9%) | 26 (32.9%) | 42 (40.0%) |
| DNR | 59 (32.1%) | 31 (30.7%) | 28 (33.7%) | 35 (44.3%) | 24 (22.9%) |
| Not documented | 57 (31.0%) | 31 (30.7%) | 26 (31.3%) | 18 (22.8%) | 39 (37.1%) |
Survival
The median follow-up time from Phase 1 trial initiation to death was 26.5 months, and it was higher at site 2 than site 1 (32.3 vs. 19.4 months, p = 0.006).
Aim 4 evaluated the impact of the intervention group, as compared with the UC group on overall survival. Overall survival was estimated by using the Kaplan–Meier method, and it was stratified by study arm (Fig. 3). We found overall survival to be comparable between intervention and control groups (log-rank p = 0.22). The median overall survival for the entire cohort was 10.1 months (95%CI: 8.4–11.9), and it reflects the typical overall survival for patients enrolled on a Phase I study.30–33
FIG. 3.
Overall survival by study arm.
Satisfaction with the patient teaching in the PCI
Overall satisfaction with the patient teachings was high. Patients rated the content (72% extremely helpful), format (79% extremely helpful), effectiveness (86% extremely helpful), and communication (76% extremely helpful); 97% reported the quantity of information to be the right amount. There was no difference at site 1 or site 2.
Dropouts
We examined patients who dropped out of the study before their 12-week assessment, by comparing their baseline characteristics with those of patients completing at least 12 weeks on the study (Table 5). We found the two populations to be essentially similar with respect to demographic and socioeconomic characteristics. The only difference seen between the two subgroups was a slightly higher rate of pancreatic cancer patients among the dropout group, which may be expected given the relatively shorter survival time for the disease compared with most other cancers.
Table 5.
Baseline Characteristics of Patients Who Completed ≥12 Versus <12 Weeks on Study
| Pts with ≥12W on study (n = 310) | Pts who dropped out <12W (n = 169) | |
|---|---|---|
| Treatment arm | ||
| Experimental | 158 (51.0%) | 82 (48.5%) |
| Control | 152 (49.0%) | 87 (51.5%) |
| Age | 60.7 (11) | 60.4 (12) |
| Gender | ||
| Female | 183 (59.0%) | 89 (52.7%) |
| Male | 127 (41.0%) | 80 (47.3%) |
| Race/ethnicity | ||
| African American | 20 (6.5%) | 14 (8.3%) |
| Asian | 30 (9.7%) | 16 (9.5%) |
| Caucasian | 210 (67.7%) | 122 (72.2%) |
| Hispanic Latino | 32 (10.3%) | 11 (6.5%) |
| Native Hawaiian | 5 (1.6%) | 1 (0.6%) |
| Mixed race | 9 (2.9%) | 3 (1.8%) |
| Other | 4 (1.3%) | 2 (1.2%) |
| Education, N (%) | ||
| Did not complete high school | 4 (1.3%) | 3 (1.8%) |
| High school | 67 (21.6%) | 42 (24.9%) |
| College | 178 (57.4%) | 80 (47.3%) |
| Graduate/professional school | 53 (17.1%) | 43 (25.4%) |
| No response | 8 (2.6%) | 1 (0.6%) |
| Religion, N (%) | ||
| None | 56 (18.1%) | 23 (13.6%) |
| Protestant | 121 (39.0%) | 65 (38.5%) |
| Catholic | 92 (29.7%) | 49 (29.0%) |
| Jewish | 16 (5.2%) | 12 (7.1%) |
| Other or no response | 25 (1.9%) | 20 (2.4%) |
| Marital status, N (%) | ||
| Never married | 9 (2.9%) | 12 (7.1%) |
| Married/living with partner | 223 (71.9%) | 136 (80.5%) |
| Divorced/separated | 51 (16.5%) | 13 (7.7%) |
| Widowed | 24 (7.7%) | 8 (4.7%) |
| No response | 3 (1.0%) | 0 (0.0%) |
| Other members, N (%) | ||
| None (lives alone) | 42 (13.5%) | 17 (10.1%) |
| Spouse | 132 (42.6%) | 81 (47.9%) |
| Children | 21 (6.8%) | 4 (2.4%) |
| Friend | 15 (4.8%) | 7 (4.1%) |
| Multiple relatives/friends | 97 (31.3%) | 60 (35.5%) |
| No response | 3 (1.0%) | 0 (0.0%) |
| Employment status, N (%) | ||
| Employed full time | 68 (21.9%) | 46 (27.2%) |
| Employed part time | 37 (11.9%) | 17 (10.1%) |
| Homemaker | 20 (6.5%) | 13 (7.7%) |
| Retired | 126 (40.6%) | 65 (38.5%) |
| Unemployed/student | 53 (17.1%) | 27 (16.0%) |
| No response | 6 (2.0%) | 1 (0.6%) |
| Family income, N (%) | ||
| $10,000 or less | 4 (1.3%) | 3 (1.8%) |
| $10,001 to $20,000 | 6 (1.9%) | 4 (2.4%) |
| $20,001 to $30,000 | 13 (4.2%) | 4 (2.4%) |
| $30,001 to $40,000 | 14 (4.5%) | 13 (7.7%) |
| $40,001 to $50,000 | 70 (22.6%) | 28 (16.6%) |
| Greater than $50,000 | 184 (59.4%) | 105 (62.1%) |
| No response | 19 (6.1%) | 12 (7.1%) |
| Type of cancer,*N (%) | ||
| Bladder | 11 (3.5%) | 2 (1.2%) |
| Breast | 25 (8.1%) | 13 (7.7%) |
| Cervical | 7 (2.3%) | 2 (1.2%) |
| Colon | 47 (15.2%) | 33 (19.5%) |
| Lung | 52 (16.8%) | 21 (12.4%) |
| Ovarian | 27 (8.7%) | 15 (8.9%) |
| Pancreatic | 13 (4.2%) | 29 (17.2%) |
| Prostate | 17 (5.5%) | 4 (2.4%) |
| Rectal | 18 (5.8%) | 10 (5.9%) |
| Other | 93 (30.0%) | 40 (23.7%) |
| Current and previous surgical procedure, N (%) | ||
| Yes | 233 (75.2%) | 112 (66.3%) |
| No | 74 (23.9%) | 53 (31.4%) |
| No response | 3 (1.0%) | 4 (0.2%) |
| Current and previous chemotherapy, N (%) | ||
| Yes | 264 (85.2%) | 158 (93.5%) |
| No | 42 (13.5%) | 9 (5.3%) |
| No response | 4 (1.3%) | 2 (0.1%) |
| Current and previous radiation therapy, N (%) | ||
| Yes | 141 (45.5%) | 71 (42.0%) |
| No | 158 (51.0%) | 91 (53.8%) |
| No response | 11 (3.5%) | 7 (4.1%) |
| Tried alternative therapies, N (%) | ||
| Yes | 63 (20.3%) | 57 (33.7%) |
| No | 235 (75.8%) | 108 (63.9%) |
| No response | 12 (3.9%) | 4 (0.2%) |
| Number of comorbidities | 1.8 (1.5) | 1.5 (1.3) |
Statistically significant difference between groups (p < 0.05), with Fisher's exact test.
Discussion
This large randomized trial of a PC intervention showed a positive impact on the main outcome variable, psychological distress, as we saw a significantly larger reduction in the PCI versus control patients over time (−0.47, p = 0.015). Further, we observed a larger increase in EWB (FACT-G subscale) among PCI versus control patients (0.81, p = 0.045). Symptom burden has been previously reported to increase as patients participate in clinical trials, which was also true in our study.23 We did not see significant differences between intervention and control groups in symptoms, as measured by the FACT-G physical well-being (PWB) subscale.
There were many indicators of the need for improved supportive care in this advanced disease population, including only 39.0% AD completion, low hospice referral (39.0%) and enrollment (30.7%), and late referral to hospice (mean 1.6 months before death). Hospice referral and utilization were well below national Quality Oncology Practice Improvement (QOPI) metrics.34
Unexpectedly, the impact on QOL varied substantially by site, with a larger and statistically significant improvement in FACT-G score at site 1 (5.02, p < 0.0001) but not at site 2 (−3.70, p = 0.0018). Differences were also observed with the subscales for EWB, and FWB, with site 1 being statistically significant and site 2 improved but not significantly. Likewise, psychological distress significantly improved at site 1 (−2.03, p < 0.0001) but not at site 2 (0.23, p-0.80). Although the intervention at site 2 had less effect on the primary and secondary endpoints, there was higher hospice enrollment at site 2 (44.7% compared with 21.6% at site 1). There were some differences in demographics between sites (Table 1) and institutional practices, such as code status (Table 4), which may reflect variables that could also have influenced outcomes.
The investigators made deliberate attempts to have fidelity of the intervention at both sites, with standardized training of nurses at each site, and structured IDT Meetings were attended by the research nurses and research team members from both sites twice per month throughout the study duration. Neither site had monthly scheduled visits with an expert PC team, as pioneered by Temel et al.9 Canadian researchers noted a clear “dose-intensity” relationship between the increase in the monthly rate of PC visits leading to decreased use of chemotherapy near the EOL, intensive care unit use, and hospitalizations near the EOL.6 A recent 400-patient multisite trial highlighted the difficulty in conducting multisite trials, with no difference between the PC and no-PC arms. However, 15% of PC patients received no PC visits, and only 49% of registrants completed the instruments at 12 weeks.35 Future studies may benefit from having more than two sites and also more rigorously evaluating issues of intervention fidelity. Other study designs may be considered for future trials, such as cluster randomization.
Limitations
We acknowledge there are some limitations in our findings, as the study was not powered to conduct some of the subgroup analyses that were reported, and we did not make adjustments for the multiple comparisons within these subscales (e.g., FACT-G subscale prediction models). However, we have presented those results, as we believe they may be a valuable guide for hypothesis generation in future study designs.
Conclusions
This PC intervention had a favorable effect on EWB and Psychological Distress, more so at the site with more experienced nurses doing the intervention. The survival of Phase I patients remains short, and substantial numbers never receive hospice or complete Advance Care Planning. Supporting patients as they make decisions regarding treatment options and evaluate goals of care can best be accomplished through the collaboration of oncologists and PC clinicans.36–39
Funding Information
This research is supported by a research grant from NCI, RO1 CA177562, “Integration of Palliative Care for Cancer Patients on Phase 1 Trials” (B. Ferrell, T. Smith–Co-PIs); the City of Hope Core, NCI P30CA033572, and the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Core Grant, NCI CCSG P30CA006973. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author Disclosure Statement
No competing financial interests exist.
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