Interleukin-2-Induced Cognitive/Affective/Sleep Symptoms
Condition: Metastatic Renal Cell Carcinoma; Metastatic Melanoma; High-dose Interleukin-2
MeSH terms: Carcinoma, Renal Cell
Study type: Observational

Summary: 
      -Purpose: Phase I: To test the methods, data collection and analysis in a study to evaluate
      cognitive/affective/sleep symptoms in one patient undergoing treatment with high-dose
      Interleukin-2 (IL-2) for metastatic renal cell carcinoma (RCC), their informal caregiver and
      their primary nurse.

      Phase II: A pilot study examining up to 10 IL-2 cases to describe cognitive/affective/sleep
      symptoms of patients receiving high-dose IL-2 therapy for metastatic melanoma (MM) or
      metastatic RCC in order to develop interventional studies to minimize these symptoms.

      -Aims: In this pilot, a case is comprised of the metastatic RCC patient receiving IL-2, their
      care partner, and their primary nurse. The care partner for this study will be the family
      member or friend staying with the IL-2 patient throughout treatment.

      Phase I (Evaluation of Methods and Procedures):

      One case will be examined to evaluate the methods, data collection and analysis to be used in
      this study. The aims of Phase I of this study are to: Aim 1) Evaluate recruitment and
      enrollment procedures to enroll one IL-2 case, comprised of the IL-2 patient, their care
      partner and their primary nurse; Aim 2) Evaluate administration procedures, data collected,
      and analysis of four questionnaire scales to detect the trajectory of cognition [Attentional
      Function Index and Montreal Cognitive Assessment] and affect [Hamilton Anxiety scale and
      Inventory of Depressive Symptomatology-Clinician] in the IL-2 patient from the start to the
      end of a cycle of treatment; Aim 3) Evaluate procedures, data collected and analysis of
      journal entries from the care partner who are to record their thoughts, observations, and
      feelings concerning any changes in the patient's behavior or cognition during IL-2 treatment
      every 8 hours; Aim 4) Evaluate procedures, data collected and analysis of semi-structured
      questionnaires completed by the primary nurse taking care of the patient receiving IL-2 which
      will describe any changes in behavior or cognition in the patient during their IL-2
      treatment; and Aim 5) Evaluate procedures, data collected and analysis of data of interviews
      with the IL-2 patient to further discern what symptoms endorsed on the measurement scales
      represent and how they are characterized, and interviewing the primary nurse to gain any
      additional data on cognitive/affective symptoms observed in the IL-2 patient.

      Phase II (Investigating Cognitive, Affective and Sleep Alterations in Patients Receiving high
      dose IL-2 therapy): Up to 10 additional cases will be enrolled to understand cognitive,
      affective and sleep symptoms induced from IL-2 therapy in oncology patients with MM or
      metastatic RCC, and help design future studies to ameliorate these treatment-limiting
      symptoms. The specific aims of this study are to: Aim 1) Describe cognitive (language,
      concentration, mental fatigue, confusion, attention, short-term memory, and orientation),
      affective (depression, anxiety, mood alterations), and sleep disturbance symptoms in patients
      receiving 1 to 4 cycles (up to 8-weeks) of high-dose IL-2 therapy. Aim 2) Examine observed
      patient experiences of cognitive/affective/sleep symptoms from each patient's primary care
      partner, and primary nurse during 1 to 4 cycles of IL-2 therapy. Aim 3) Describe the
      trajectories of cognitive/affective/sleep symptoms in patients with MM or metastatic RCC
      undergoing 1 to 4 cycles of IL-2 therapy. Not all patients will receive 4 cycles of IL-2,
      because treatment will depend on a) disease progression and b) side effect toxicity;
      therefore, the symptom trajectory will be described for the cycles completed in situations
      where all cycles are not completed.
    

Detailed description: 
      -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.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Eligible participants will be recruited from Duke University Hospital (Duke North) in
        Durham, NC.