Interleukin-2-Induced Cognitive/Affective/Sleep Symptoms

-Background & Significance: Alterations in cognitive, affective and sleep functioning are among the most challenging side effects experienced by 80% of patients undergoing high dose IL-2 therapy. Altered cognition includes a wide array of symptoms such as changes in concentration, attention, short-term memory, confusion, mental fatigue, executive functioning, abstraction, language, basic arithmetic, and orientation. Affective symptoms include mood alterations, depression, anxiety, psychosis, hallucinations, aggression, suicidal ideation, and coma. Sleep symptoms include the insomnias (initial, middle, delayed) and hypersomnia. Severe cognitive/affective/sleep symptoms may result in early termination of IL-2 therapy, preventing the patient from receiving its full benefits. In some patients, cognitive, affective and sleep symptoms continue throughout the remainder of their life, decreasing the quality of life for patients and their families. Although prior investigators reported chemotherapy-related altered cortical and cognitive function including slowed processing time and decreased brain activation, as well as signs of increased cytokines and decreased gray matter, studies investigating the trajectory of immunotherapy-related altered cognition have not been found in published literature. Describing the impact of IL-2 therapy on cognition, affect and sleep is essential to designing interventions to ameliorate these treatment-limiting symptoms. Because IL-2 patients receive several doses of medication over a number of days, exploring these symptoms through a trajectory analysis of these symptoms is critical. Without fully understanding the breadth and depth of IL-2-induced cognitive/affective/sleep symptoms, advances in science to alleviate these symptoms are at a standstill.

Metastatic RCC and MM are two cancers treated with IL-2, where surgery, chemotherapy and radiation therapy are ineffective for patients with stage III and IV disease. For phase I of this pilot study, we will focus only on enrolling one IL-2 patient with metastatic RCC, their care partner and their primary nurse; as many five subjects comprising one case may be recruited for consent. In 2014, the National Cancer Institute estimates 76,000 new diagnoses and 9,700 deaths secondary to melanoma, and 64,000 new cases and 14,000 deaths secondary to kidney cancer. IL-2, a cytokine based immunotherapy, is administered to patients with metastatic disease to stimulate their immune systems to fight off cancerous cells, and is one of the few treatments available for patients with progressed disease. When IL-2 is administered in high-dose, intravenous form, patients experience severe and potentially life-threatening side effects. The long-term impact of IL-2 treatments on cognitive/affective symptoms has not been documented. Despite severe symptoms and side effects, 33% of MM patients have some response to IL-2 treatment and 15% of MM patients show a complete response with no detectable metastases after treatment. In RCC, 14% of patients show some response and 8% show a complete response. Thus, interventions that help patients complete treatment are warranted and would build on knowledge gained in this study.

-Procedures: Phase I will enroll a case over one cycle of high-dose IL-2 given over five days. Phase II will enroll up to 10 additional cases for up to four cycles of high-dose IL-2 therapy. High-dose IL-2 is defined as 600,000-720,000 International Units/kilogram, administered intravenously over 15 minutes, every 8 hours for a maximum of 14 consecutive doses; these 14 doses comprise one treatment cycle. Quantitative data will be collected using questionnaires administered to the IL-2 patient measuring cognitive/affective/sleep symptoms before and after each cycle of high-dose IL-2 to describe any longitudinal changes in the patient over the therapy course. Qualitative data will be collected through semi-structured journal entries written by the care partner, semi-structured questionnaires given to the nurses after each dose of IL-2, and interviews with the IL-2 patient, care partner and primary nurse.

Three constructs (cognitive symptoms, affective symptoms, sleep symptoms) will be used to describe IL-2-induced cognitive/affective/sleep symptoms using four sources for data collection (the IL-2 patient, their primary care partner, their nurses, and their primary nurse). The index participant will receive up to three high-dose IL-2 treatments per day, at 8-hour intervals, for a maximum of 14 doses per cycle. The pattern of data collection in Phase I will repeat for a maximum of four IL-2 cycles in Phase II.

Cognitive/affective/sleep symptoms experienced by the patient will be evaluated using six scales. Scales will be administered to the index participant upon their admission to the hospital before receiving the first dose of IL-2 in each cycle, and 16-hrs after the last IL-2 dose for each cycle. The nurse caring for the IL-2 patient will be contacted over the phone and we will be in constant communication about the timing of IL-2 administration and therapy ending. Questionnaires will be administered in the patient's private hospital room. Although it would be ideal to administer these surveys following each IL-2 dose, the IL-2 patient is disrupted every four hours for IL-2 related care. Administering the scales only twice during each cycle will reduce patient burden and will be sufficient to assess for longitudinal changes in cognitive/affective/sleep symptoms. For symptoms endorsed by the patient 16-hr post-treatment, we will interview the IL-2 patient to further discern what these symptoms represent and how they are characterized. This semi-structured interview will be recorded and transcribed.

The care partner will be asked to record observations of the patient's cognitive, affective and sleep symptoms as a journal entry three times per day, prior to the first IL-2 dose and then after each dose. The semi-structured journal entry will contain a checklist to signify when symptoms are observed by the care partner, such as the patient pulling out catheters or intravenous lines, confusion, hallucinating, signs of depression, and/or anxiety. The checklist will be followed by a prompt that will read, "For the boxes you checked above, please describe the changes you witnessed. When did the symptom appear? How long did the symptom last? How severe is the symptom? Can you describe the situation? Did anything make this symptom better or worse?" Following this prompt, the final open-ended prompt will read, "If there are other changes in the patient that you feel the team should know about, please feel free to write about these changes as well." After treatment has ended, the care partner will participate in a post-treatment semi-structured interview at the end of each cycle of therapy. This interview will be recorded and transcribed.

Similar to the care partner, nurses that participate in the patient's care will receive the same semi-structured prompt as the care partner. Nurses will also be asked to write, 'I did not witness any cognitive or affective changes in the IL-2 patient during my time with the patient' if changes in symptoms were not observed. A folder containing the prompt for the nurses will be kept in a secure place on the unit for the nurses to access so they can retrieve a form containing the prompt prior to doing their nursing assessment. The nurses will be encouraged to complete the form after each IL-2 infusion. Once the primary nurse for the IL-2 patient is identified, we will approach s/he for consent and interview the primary nurse to gain any additional data on cognitive/affective/sleep symptoms observed in the IL-2 patient. This interview will be recorded and transcribed. Field notes will be collected throughout the study to enrich the data. Collection of data from multiple sources such as interviews, journal entries and field notes will allow for a comprehensive understanding of the data.