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.

Inclusion Criteria (of the IL-2 patient):

- Persons diagnosed with metastatic RCC/MM (stage III or stage IV) disease

- 18-65 years of age

- English speaking and literate

- Receiving HD IL-2 (720,000 IU/kg of IL-2 IV q8hr for a total of 14 doses per cycle)
therapy at Duke University Hospital

- Must have a care partner (family member or friend) active in their care during IL-2
treatments

Exclusion Criteria:

- Previously documented cognitive disorder

- Congenital brain defects

- Traumatic brain injuries

Primary care partner: defined as the primary family member or friend who will be staying
with the patient at the hospital during the patient's IL-2 therapy OR is active in the
patient's care. The IL-2 patient may have up to two primary care partners, for example a
care partner for nights/days or alternating days. Care partners who are under 18 years may
enroll if their parent is the IL-2 patient. For this study, the care partner must be at
least 16 years old in order to participate because of the nature of the study. Their
parent must be present and must consent for enrollment.

Primary Nurse: will be identified by the unit or self-identified as the nurse who best
"knows" the patient and his/her care. The primary nurse must be a Registered Nurse.