Periodic Reporting for period 1 - PaSION (A longitudinal assessment of treatment experience, symptoms and potential associations with biomarkers in cancer patients undergoing immune checkpoint inhibitor therapy)
Periodo di rendicontazione: 2018-09-01 al 2020-08-31
PaSION (Patient Symptoms in Immuno-Oncology) is a nurse-led study designed as an exploratory, longitudinal and observational research in a single center (Department of Oncology at the Lausanne University Hospital, DO-CHUV). Using semi-structured interviews, self-reported questionnaires, health-related personal data, and newly sampled blood, we aim to gain a more complete understanding of patients’ experience during the first months of immune-checkpoint inhibitors (ICI) therapy. In addition, we investigate potential associations between symptoms reported by the patient and immune-related biomarkers that might predict and prevent adverse events.
ICIs have shown significant clinical benefit in a growing number of different tumor types. Because ICI drugs target cells of the immune system, this therapy can lead to toxicities associated with inflammatory or autoimmune responses, known as immune-related adverse events (irAEs). Importantly, up to 85% of patients experience irAEs of any grade. Although rare, even fatal toxicities may occur, and therefore, prompt recognition and management is important. Taking the increasing use of these therapies in the clinical practice into account, it has been of urgent interest to achieve a comprehensive understanding of the overall patients' experience during ICI therapy, including symptomatic toxicities and quality of life.
Patient-Reported Outcomes (PROs) allow the identification of benefits or deficiencies related to the disease or treatment that are only detectable by the patient and can be collected through questionnaires, diaries or interviews. For instance, PROs permit to quantify symptom severity and frequency, or their impact on patient's function, but also more complex concepts such as quality of life (QoL). Studies show that PROs are more concordant with the patient’s overall health status and result in earlier detection of toxicity/symptom occurrence and severity compared to clinician reports. Thus, given the importance of early detection in irAEs, PRO assessment could serve as a complementary indicator for ICI toxicities before the presentation of any severe clinical manifestation. Furthermore, evidence has proven the association of cytokine levels with several symptoms and their use as therapy-related toxicity predictors before treatment initiation.
In order to achieve the overall objective, four major research questions were proposed through a series of independent, yet complementary aims.
AIM 1: To identify and examine instruments currently used to measure PROs in ICI therapy.
AIM 2: To describe the treatment experience of patients undergoing ICI therapy.
AIM 3: To explore potential associations between selected immune-related biomarkers and the most frequent symptoms reported by patients undergoing ICI therapy.
AIM 4: To adapt an existing PRO instrument or develop a novel immune oncology (IO)-specific measure.
ICIs have shown significant clinical benefit in a growing number of different tumor types. Because ICI drugs target cells of the immune system, this therapy can lead to toxicities associated with inflammatory or autoimmune responses, known as immune-related adverse events (irAEs). Importantly, up to 85% of patients experience irAEs of any grade. Although rare, even fatal toxicities may occur, and therefore, prompt recognition and management is important. Taking the increasing use of these therapies in the clinical practice into account, it has been of urgent interest to achieve a comprehensive understanding of the overall patients' experience during ICI therapy, including symptomatic toxicities and quality of life.
Patient-Reported Outcomes (PROs) allow the identification of benefits or deficiencies related to the disease or treatment that are only detectable by the patient and can be collected through questionnaires, diaries or interviews. For instance, PROs permit to quantify symptom severity and frequency, or their impact on patient's function, but also more complex concepts such as quality of life (QoL). Studies show that PROs are more concordant with the patient’s overall health status and result in earlier detection of toxicity/symptom occurrence and severity compared to clinician reports. Thus, given the importance of early detection in irAEs, PRO assessment could serve as a complementary indicator for ICI toxicities before the presentation of any severe clinical manifestation. Furthermore, evidence has proven the association of cytokine levels with several symptoms and their use as therapy-related toxicity predictors before treatment initiation.
In order to achieve the overall objective, four major research questions were proposed through a series of independent, yet complementary aims.
AIM 1: To identify and examine instruments currently used to measure PROs in ICI therapy.
AIM 2: To describe the treatment experience of patients undergoing ICI therapy.
AIM 3: To explore potential associations between selected immune-related biomarkers and the most frequent symptoms reported by patients undergoing ICI therapy.
AIM 4: To adapt an existing PRO instrument or develop a novel immune oncology (IO)-specific measure.
To address AIM 1, we performed a systematic review of published literature to identify and categorize the types and combination of PRO instruments used in clinical trials involving cancer patients receiving ICI therapy (ICI-CTs). To further examine the content validity of the PRO instruments, we identified and compared the most frequent AEs reported in ICI-CTs with published PRO results. We identified 191 ICI clinical trials stating the use of PRO measures of which 26 published PRO results. Cancer-specific and generic health status questionnaires were the most widely used instruments, often in combination with disease-specific PROs. Instruments used to report symptomatic toxicities covered 45% of the most frequently reported AEs, whereas almost half of AEs were partially covered or not covered at all. We concluded that despite the high frequency of symptom-related irAEs, these events are only partially covered (or not addressed) by current PRO instruments, even when combined.
Regarding the progress for AIM 2 and AIM 3, 34 patients have been recruited to date, of which 18 have completed the study (six up to week 13, and 12 up to week 25), seven patients stopped earlier, and seven patients are still active in the study.
The objective of AIM 2 is to gain a better understanding of patients’ experiences during the course of their treatment and to investigate whether the current PRO instruments reflect the needs of patients treated with ICIs. A preliminary analysis of the interviews at baseline identified four main themes: Facing the diagnosis, Impact of the disease and treatment, Knowledge about the treatment, and Expectations regarding the treatment. Analysis of the other time points is ongoing. The final analysis of the complete data set will include a comparison about how the thematic groupings change -or not- over time. In addition, we will compare themes identified through the interviews with the EORTC QLQ-C30 questionnaire to identify new aspects not covered by this instrument.
AIM 3 comprises the quantitative data collection of symptoms and biomarkers. Analysis of symptom questionnaires will be explored in two dimensions: (i) longitudinally per patient, and (ii) cross-sectionally per time point. In addition, we will explore the evolution of the biomarkers and immune cell subsets along the treatment and investigate whether changes in their concentrations might be associated with the appearance, increase or decrease in the severity of symptoms reported by the patients. Analysis of these datasets will be performed once data collection is completed.
In AIM 4, we aim to evaluate the need for adaptation of an existing instrument or for the development of new PRO measures in the context of ICI treatments. Using an adapted Delphi technique, a panel of international oncology experts was created to identify and prioritize the integration of new and existing PRO-CTCAE items relevant for ICI symptomatic toxicities into electronic PRO forms.
Results of this project have been presented at several scientific meetings at the national and international level (Swiss Oncology Nursing Conference 2018 & 2020, ESMO-EONS 2018 & 2020, MASCC 2019). A publication containing results of AIM 1 is available open-access at the Journal of Patient-Reported Outcomes (doi:10.1186/s41687-020-00210-z).
Regarding the progress for AIM 2 and AIM 3, 34 patients have been recruited to date, of which 18 have completed the study (six up to week 13, and 12 up to week 25), seven patients stopped earlier, and seven patients are still active in the study.
The objective of AIM 2 is to gain a better understanding of patients’ experiences during the course of their treatment and to investigate whether the current PRO instruments reflect the needs of patients treated with ICIs. A preliminary analysis of the interviews at baseline identified four main themes: Facing the diagnosis, Impact of the disease and treatment, Knowledge about the treatment, and Expectations regarding the treatment. Analysis of the other time points is ongoing. The final analysis of the complete data set will include a comparison about how the thematic groupings change -or not- over time. In addition, we will compare themes identified through the interviews with the EORTC QLQ-C30 questionnaire to identify new aspects not covered by this instrument.
AIM 3 comprises the quantitative data collection of symptoms and biomarkers. Analysis of symptom questionnaires will be explored in two dimensions: (i) longitudinally per patient, and (ii) cross-sectionally per time point. In addition, we will explore the evolution of the biomarkers and immune cell subsets along the treatment and investigate whether changes in their concentrations might be associated with the appearance, increase or decrease in the severity of symptoms reported by the patients. Analysis of these datasets will be performed once data collection is completed.
In AIM 4, we aim to evaluate the need for adaptation of an existing instrument or for the development of new PRO measures in the context of ICI treatments. Using an adapted Delphi technique, a panel of international oncology experts was created to identify and prioritize the integration of new and existing PRO-CTCAE items relevant for ICI symptomatic toxicities into electronic PRO forms.
Results of this project have been presented at several scientific meetings at the national and international level (Swiss Oncology Nursing Conference 2018 & 2020, ESMO-EONS 2018 & 2020, MASCC 2019). A publication containing results of AIM 1 is available open-access at the Journal of Patient-Reported Outcomes (doi:10.1186/s41687-020-00210-z).
PaSION is an innovative study. First, PaSION is a nurse-led research project combining three different approaches (i.e. qualitative research, PRO questionnaires, and biomarkers). By triangulating all this information, we will gain a broader understanding about the experience of patients treated with ICIs. Second, to date, most published studies have correlated biomarkers with adverse events reported by physicians, mostly in the context of clinical trials. Using symptoms reported by the patients will provide a new insight into ICI toxicities, maybe not the most severe ones, but the ones interfering the most with the patients’ daily life. Third, this project has been a precious opportunity to establish an interdisciplinary collaboration between different stakeholders (patients, caregivers, healthcare professionals, laboratory technicians and administrative staff).
Results from this project will have wide-reaching impact related to the combination of approaches and methodology used. Most importantly, results of the study (identification of the needs, concerns, symptoms, and symptom burden) may help clinical oncology teams to develop a more patient-centred approach in the future.
Results from this project will have wide-reaching impact related to the combination of approaches and methodology used. Most importantly, results of the study (identification of the needs, concerns, symptoms, and symptom burden) may help clinical oncology teams to develop a more patient-centred approach in the future.