Use of the PALLIA 10 Score in Patients Enrolled in Phase I Trials at Gustave Roussy Cancer Center

Early phase clinical trials usually include patients with advanced disease who have failed standard therapies. Early palliative care for these patients has shown to improve quality of life and even survival. PALLIA 10 score (ranging from 1 to 10) is a tool developed by the French Palliative Care Society to identify the best time to introduce palliative care. We assessed the PALLIA 10 score and other prognostic factors (age, ECOG, Royal Marsden Hospital (RMH) score, LDH and albumin levels, number of prior systemic treatments and metastatic sites) in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during 2 periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done during 15 days by a member of the palliative care unit in C2. A PALLIA 10 > 3 motivated a dedicated palliative care consultation.


Abstract Background
Early phase clinical trials usually include patients with advanced disease who have failed standard therapies. Early palliative care for these patients has shown to improve quality of life and even survival. PALLIA 10 score (ranging from 1 to 10) is a tool developed by the French Palliative Care Society to identify the best time to introduce palliative care.

Methods
We assessed the PALLIA 10 score and other prognostic factors (age, ECOG, Royal Marsden Hospital (RMH) score, LDH and albumin levels, number of prior systemic treatments and metastatic sites) in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during 2 periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done during 15 days by a member of the palliative care unit in C2. A PALLIA 10 > 3 motivated a dedicated palliative care consultation.

Results
From July 1st 2018 to November 1st 2018 (C1) and from December 1st 2020 to April 16th 2021 (C2), a total of 86 patients were assessed in C1 and 302 in C2. No difference was observed between the two cohorts regarding prognostic factors. Median PALLIA 10 was also similar and very low (median 1, range 1-5 in C1 and 1-8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation.
Overall, 77% and 74% of patients in C1 and C2 were still alive beyond 3 months after discontinuation of the trial (p=0.78), followed by at least one subsequent treatment in 63% and 70% of pts. In C2,

Introduction
Multiples studies have demonstrated that early palliative care enhances quality of life with fewer refractory symptoms but also improved survival in patients with advanced cancer(1-4), leading to the integration of supportive and palliative care as a pillar in the guidelines of several oncology organizations such as the American Society of Clinical Oncology (ASCO) (5) or the European Society of Medical Oncology (ESMO) (6) for the management of cancer patients with advanced disease.
Diverse clinical and biological markers can be used as prognostic and predictive factors for cancer patients (7)(8)(9). However, there is currently no validated tool to help clinicians to identify the patients who might bene t from a palliative care consultation and determine the best time to refer them. The French palliative care society (SFAP) tried in this context to create a tool, named PALLIA 10, a score composed of ten questions, evaluating multiples aspects of the patient's daily life, ranging from the presence of physical or psychological refractory symptoms to the evolution and the comprehension of the stage of the disease. The questionnaire is intended for patients who cannot be cured; a positive reply to each item leads to an extra point, leading to a score ranging from 1 to 10 (Supplementary Data). An assessment by the palliative care team is considered required if the score is >3. PREPA 10, a multicenter study performed in 18 cancer centers in France, has concluded that the PALLIA 10 score might be a prognostic and predictive factor of death within 6 months if it was superior at 3 (10).
Phase I trials are usually known to recruit patients with advanced disease who have failed standard therapy and thus might bene t from early palliative care (11,12). Although there has been an improvement in objective response rate in phase I trials between the early 2000's and now, from 10 (13) to nearly 20% (14), the clinical bene t might still not be enough for those patients. We aimed to evaluate if PALLIA 10 could be used in our phase I department at Gustave Roussy Cancer Center in order to address patients who will bene t from a palliative care follow-up.

Patients
We included prospectively patients included in early clinical trials in our institution during two-time ranges in 2018 and in 2020/21. In the 2018 cohort (C1), only patients who were beginning the trial during our period of analysis were included, while in the 2020/21 (C2) patients who were already on treatment were also evaluated. PALLIA 10 score was realized by a phase I physician for all the patients included in both cohorts. We reported different other prognostic factors for each patient from their medical records: age, ECOG, LDH (lactate deshydrogenase) and albumin levels, number of prior systemic treatments and metastatic sites. Royal Marsden Hospital (RMH score), a validated phase I prognostic score, composed of 3 of these items (LDH and albumin levels and number of metastatic sites) was also evaluated (15). Overall survival was assessed as well as subsequent lines of treatment after discontinuation of the trial.
The aim of using two cohorts was to see if there was any changes in terms of prognostic factors in the 2year period for patients included in phase I trial and to assess whether the fact that different physicians were assessing the patients led to differences in PALLIA10 score.

Palliative care referral
We evaluated if patients were referred to a palliative care team during their follow-up and the time between the beginning of the trial and the rst palliative care evaluation.

Double blind study
In the second cohort, we realized a double-blind assessment of PALLIA 10 score by a phase I physician and a palliative care specialist during a rst 15-days period. We then repeated this practice in a second 15-days period within C2 adding a phase I nurse evaluation.

Statistics
Descriptive statistics were used to describe patient characteristics. Comparison between the two cohorts were done using a chi-2 test, overall survival was evaluated with a Log Rank test. Statistics were made using GraphPad Prism 9.

Objectives
The primary objective was to assess if the PALLIA 10 score could be used in our phase I department as a tool to select patients who will bene t from a palliative care referral. The secondary objective was to nd out whether the patients evolved over the 2-year period in terms of clinical pro l and prognostic factors.

Patient characteristics
During the 2018 cohort (C1), a total of 86 patients were included in our study from July 1st 2018 to November 1st 2018, while 302 were evaluated in C2 between December 1st 2020 and April 16th 2021.
Gastro-intestinal (23%), hematological (14%), genito-urinary (12%) and lung (11%) cancers were the most frequent tumor types. As expected in early clinical trial, most patients had an ECOG of 0 or 1 and had already received ≥ 3 lines of therapy (Table 1). Two patients in C1 and one in C2 already had seen the palliative care team before beginning the trial.   Pallia 10 assessment Median time to PALLIA 10 assessment from time to trial onset was 15.5 days [0-1874] in C2 while it was only done on the rst day of treatment in C1. Median PALLIA 10 score was of 1 in the two cohorts (range in C1: 1-5 and 1-8 in C2, p=0.06). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation respectively (p=0.024) with a median time of referral of 18 and 2 months after the trial onset (p=0.055) and a median PALLIA 10 score of 1.5 and 2 (p=0.65), respectively.

Outcomes
Overall, at data cut-off (August 1st 2021), 94% (C1) and 60% (C2) of the patients had progressive disease and stepped out of the trial. Among those, 77% and 74% were still alive 3 months after discontinuation of the study (p = 0.78) ( Figure 1) and 63% and 70% had at least one subsequent line of treatment in C1 and C2.
Median OS was 10 months in C1 and not reached in C2.

Double blind Pallia 10 assessment
The rst double blind study done within C2 between November 1st 2021 and January 22nd 2021 involved the evaluation of 25 patients and showed that PALLIA 10 score what signi cantly higher when done by a palliative care specialist than by the phase I physician (median score of 1 and 4, p<0.001). Likewise, the assessment of the score from April 12th 2021 to April 23rd 2021 for 37 patients demonstrated a higher median PALLIA 10 when it was realized by a palliative care physician than by a phase I nurse and a phase I physician (median score of 5, 3 and 1, p<0.001) (Figure 2). There was no correlation between a score >3 and survival at three months whether it was performed by a phase I physician (p=0.09), a phase I nurse (p=0.16) or a palliative care physician (p=0.39).

Discussion
Our study showed that the use of the PALLIA 10 score in an early clinical trial department might not be as suitable as it is to help address patients to a palliative care consultation.
In our study, PALLIA 10 score was very low, with a median score of 1 in both cohorts when it was done by a phase I physician, while it was slightly higher when assessed by a phase I nurse or a palliative care specialist. Several studies have shown that it is a challenge for oncologists to call upon a palliative care team for their patients. A national American study involving 4 focus groups of medical oncologists deduced that while oncologists know and value the concept of early palliative care they were afraid that palliative care teams might interfere with the plan of care, mainly to propose to stop active treatments despite the opinion of the oncologist (16). A systematic review of 23 studies on the subject also concluded that the main reason for oncologists not wanting to refer their patients to a palliative care team was to stay in control of the treatment plan, but also the fear of rupture of the therapeutic alliance and creating a loss of hope for the patients. The lack of referral criteria and the limited number of palliative care specialist were also additional arguments (17). One could therefore think that one of the reasons for the low scores in our study was the fear of palliative care intervention, for instance by trying to discontinue the patient's trial. However, a study evaluating changes in quality of life for patients in phase I or II trials showed no difference in terms of number of cycles of treatments achieved in the arm receiving standard of care and the one integrating a palliative care program. Likewise, their research didn't affect the patient's and the physician's relationship (18). Another research done in California evaluating the incorporation of palliative care for 14 patients undergoing early clinical trials demonstrated the feasibility of palliative care intervention in this background, resulting in a sustainability of syndrome distress in a 3 months period of time (19). Patients also often have a awed vision of palliative care assimilating it to end of life care only. A randomized control trial of early palliative care or standard of care conducted on patients with advanced cancers demonstrated that initially most of the patients equated palliative care to death or anxiety, but patients in the intervention arm changed their view on the subject during the trial connecting it to a better quality of life, which emphasizes the need to better educate the patients and promote palliative care (20). Furthermore, patients might put a lot of hope in phase I trial and be afraid to highlight symptoms to phase I physicians and have to discontinue the protocol. A report on 69 patients in phase I trials and 297 included in phase II or III trials deduced that patients in early clinical trials had a higher symptom burden but were less likely to seek for care services (12).
There was no difference observed in the two cohorts of patients regarding standard prognostic factors. While a difference was observed relating to albumin levels, it might be explained by a change in dosage in our local laboratory between the two assessments. There was also no difference in PALLIA10 evaluation between 2018 and 2020/21 while the physicians conducting the assessments had changed during the two-year period, which emphasizes the fact that a palliative evaluation does not depend on individuals but rather on professions' groups as mentioned above, and suggest the need to educate in particular phase I physician in palliative care. In our study, we did not nd a correlation between a score >3 and overall survival, in contrast to the original study in which pallia 10 was a prognostic factor for survival. This difference may be due to a too short follow-up in C2, but also to the fact that the PALLIA 10 in the original study was performed by palliative care physicians and not by oncologists (10). Finally, 23% and 26% of the patients in C1 and C2 died 3 months after discontinuation of the study but only few were addressed to our palliative care team which highlight the need for a better evaluation of the patients. While our study didn't report any data regarding change in quality of life, a randomized control trial on 68 patients included in early clinical trials showed fewer adverse events and better quality of life for patients receiving palliative care than those in the control group (21).
Nurse's evaluation of the PALLIA 10 score was better than that of the phase 1 physician in our study which is concordant with what we expected. As they usually spend more time with the patients than the clinicians their interaction with the patients allows them a better grasp on patients' symptoms and perceptions. An evaluation of patients' reported adverse event using the National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) showed that the nurses' assessments were more relevant to the patients' that those of the clinicians, especially regarding asthenia, constipation, neuropathy, mucositis and diarrhea (22). The same conclusion was drown from another report also using CTCAE that highlights a difference in symptoms' grading between physicians and patients when it comes to subjective symptoms such as fatigue or dyspnea (23). Both those studies also emphasize the possibility to revise caregiver questionnaires in order to make them comprehensible to the patient's which allows us to have the most accurate evaluation possible. In the current time, with the development of multiples digital tool in oncology, the use of patients-reported outcome (PRO) might seem to be a great alternative to caregiver's evaluation to better assess the patients' symptoms and understanding of its cancer and ultimately to allow the selection of those who need early palliative care. Currently, only few studies evaluated the incorporation of PRO in a phase I setting but with promising (24,25). Larger studies on the subject are essential to improve our patients' care.

Conclusion
Only few patients were addressed to the palliative care team within the two period of time. Median PALLIA 10 was systematically low when assessed by the phase I physician even for the patients who were seen by a palliative care specialist. There was no signi cant change in other prognostic factors in the 3 years-period between the two cohorts. The development of an appropriate score to enable patient self-assessment using PRO could be a solution to better understand and select patients for palliative care support. Overall survival at discontinuation of the phase I trial in cohort 1 (C1) and cohort 2 (C2) Figure 2 Assessment of PALLIA 10 in a double bling setting by the phase I physician/palliative care specialist (a) then by the phase I physician/palliative care specialist/ phase I nurse (b) in cohort 2 (C2)