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Cognitive and Affective Symptoms Experienced by Cancer Patients Receiving High-Dose Intravenous Interleukin 2 Therapy

An Integrative Literature Review

Mann, Tara K. BSN, RN; Dail, Robin B. PhD, RN, FAAN; Bailey, Donald E. Jr PhD, RN, FAAN

doi: 10.1097/NCC.0000000000000317

Background: Alterations in cognitive/affective functioning are among the most challenging adverse effects experienced by 80% of patients with metastatic melanoma and metastatic renal cell carcinoma undergoing high-dose interleukin 2 (IL-2) therapy.

Objective: The purpose of this literature review is to describe what is known about IL-2–induced cognitive/affective symptoms, their prevalence, and level of severity and synthesize findings to determine areas for future research to address symptom management challenges. This review describes the IL-2 patient experience and the pathophysiology leading to these changes.

Methods: An online electronic search using PubMed was performed to identify relevant literature published between 1992 and 2015. Of the original 113 articles, information was extracted from 9 articles regarding cognitive symptoms, affective symptoms, sample size, research design, reliability, and validity.

Results: Our review suggests that the trajectories, breadth, and depth of cognitive/affective symptoms have yet to be described. Despite intervention studies designed to address the psychosocial complications of IL-2, an understanding of the level of altered cognitive/affective symptoms experienced by IL-2 patients remains unclear.

Conclusion: Our literature review reveals a lack of standardization when assessing, reporting, and managing cognitive/affective symptoms. Patients/family members have reported cognitive/affective symptoms to be the most alarming and difficult symptoms, yet these symptoms are not adequately screened for, and patients were not informed about potential changes.

Implications for Practice: Assessing patients for cognitive/affective alterations is important to reduce anxiety while improving outcomes. Education about the illness trajectory (what to expect during/after treatment) can help care partners/patients set realistic shared expectations and increase coping.

Author Affiliation: School of Nursing, Duke University, Durham, North Carolina.

This work was supported in part by the National Institute of Nursing Research (NIH P30NR014139); S.L. Docherty and D.E. Bailey Jr. are principal investigators, Duke University School of Nursing.

The authors have no conflicts of interest to disclose.

Correspondence: Tara K. Mann, BSN, RN, School of Nursing, Duke University, DUMC 3322, Room 3080, 307 Trent Dr, Durham, NC 27710 (

Accepted for publication September 4, 2015.

Alterations in cognitive and affective functioning are among the most challenging adverse effects experienced by 80% of patients with metastatic melanoma (MM) and metastatic renal cell carcinoma (RCC) undergoing high-dose interleukin 2 (IL-2) therapy.1 Altered cognition2 includes changes in concentration, attention, short-term memory, confusion, mental fatigue, executive functioning, abstraction, language, and basic arithmetic and orientation,3,4 whereas affective symptoms2 include mood alterations, depression, anxiety, psychosis, hallucinations, aggression, suicide ideation, and coma.5–7 Severe cognitive/affective symptoms may result in early termination of IL-2 therapy, preventing the patient from receiving a therapeutic dose, decreasing the quality of life for patients and their informal caregivers. Furthermore, these cognitive and affective symptoms are seemingly difficult for providers to manage. In some patients, cognitive and affective symptoms continue throughout the remainder of their life.7 Because nurses are routinely assessing patients and therefore can quickly identify acute changes, educating nurses in addition to family members could be beneficial in assessing for and reporting alterations in cognition and affect. Early detection of cognitive/affective symptoms will allow for all care providers to intervene earlier, potentially reducing stress and anxiety in patients and their family members, while also allowing patients to receive more therapy.

Although cognitive and affective symptoms experienced by IL-2 patients have not been extensively studied, research that has been conducted show these symptoms have a profound negative impact on patients, families, and providers.8 Furthermore, many of the symptoms patients and their family members describe have not been measured and disseminated in published literature. One patient described his experience with depression and anxiety:

On Monday, I became extremely depressed and felt a lot of panic. Panic in breathing, and in the efficacy of the treatment. I spent the day unable to think about anything but that, and it was a pretty dark day. Tuesday was more of the same, with a few more brain cells firing on different things but still worry and panic. …Though I had read about the adverse effects of IL-2, I saw more the physical adverse effects and didn’t really consider the mental ones. I am here to tell you that they are as debilitating as the physical ones and not to be underestimated.9

In 2015, the National Cancer Institute (NCI) estimated 73 870 new diagnoses and 9940 deaths secondary to melanoma10 and 61 560 new cases and 14 080 deaths secondary to kidney cancer.11 The US Food and Drug Administration approved the use of IL-2 in cancer patients in 1992.12 Patients with MM and metastatic RCC are treated with high-dose IL-2 therapy when surgery, chemotherapy, and radiation therapy have been ineffective for those with stages III and IV disease. Interleukin 2, a cytokine-based immunotherapy, is given to patients with metastatic disease to stimulate their immune systems to fight off cancerous cells13 and is one of the few treatments available for these patients.12 Interleukin 2 is a therapy shown to be beneficial specifically for clear cell RCC patients with metastatic disease, where 94% of clear cell RCC patients have carbonic anhydrase IX, an RCC marker associated with better IL-2 outcomes.14 When IL-2 is administered in high-dose, intravenous form, patients experience severe adverse effects.1,13,15–22 Thus far, the long-term impact of IL-2 treatments on cognition and affect has not been thoroughly described. Depression has been measured a month after the cessation of IL-2 therapy,23 yet longitudinal studies of symptoms following treatment are absent in published literature. Several studies have identified cognitive (fatigue,15,24,25 confusion or disorientation,15,17 seizures,1,22 mental status changes1) and affective (depression,23,26 hallucinations,22 coma1,15,17) symptoms. These studies grade the severity of these symptoms; however, absent from the literature are descriptions of when and how these symptoms present and how they change over time. Despite severe symptoms and adverse 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.16,27 In RCC, 14% of patients show some response, and 8% have a complete response.27,28 Therefore, it is important to understand the depth and breadth of cognitive/affective symptoms to help patients, families, and providers mange these symptoms so the patient might complete the full course of therapy.

High-dose IL-2 is defined as 600 000 to 720 000 IU/kg, which is administered intravenously over 15 minutes, every 8 hours for a maximum of 14 consecutive doses; these 14 doses comprise 1 of up to 4 treatment cycles.15 Despite the benefits of IL-2, managing the adverse effects of this treatment continues to pose a challenge for patients, family members, and providers. One patient explained:

There was extreme mental craziness… I couldn’t sleep, I paced the floor over and over, my brain was fried—even with sleep medication, the dreams I had were just terrifying. I wasn’t vocal enough with the medical staff about the things I was experiencing either. I was disoriented—and bewildered.29

These quotes from patients and families highlight the importance of uncovering and understanding the wide array of cognitive and affective symptoms that patients receiving high-dose IL-2 therapy experience.

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The purpose of this literature review is to describe what is known about IL-2–induced cognitive/affective symptoms, their prevalence, and level of severity and synthesize findings to determine areas for future research to address the challenges experienced by patients, family members, and providers resulting from these symptoms. Patients receiving IL-2 therapy might tolerate more treatment, attain better response rates, and achieve better quality of life if life-threatening adverse effects are managed or reduced. This literature review describes the patient experience when undergoing high-dose IL-2 and the pathophysiology leading to these changes.

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PubMed was used to identify relevant literature describing IL-2–induced cognitive/affective symptoms. Table 1 depicts the search filters, search term combinations, and articles returned for each search. Results were limited to articles published after 1992, the year the Food and Drug Administration first approved IL-2 for cancer treatment.

Table 1

Table 1

The 113 search results from PubMed were imported into EndNote X6, and 38 duplicates were removed. The titles and abstracts of the 75 remaining articles were reviewed, and reasons for exclusion are shown in the Figure. The bibliographic snowball technique was used to locate 5 additional articles for inclusion.30 The 20 remaining articles along with the 5 additional articles were reviewed in full text. Studies of cancers other than melanoma and RCC were excluded because standard of care dictates that IL-2 is effective only in treating patients with these specific cancers. Nine articles were retained that met inclusion criteria for the review.



The Matrix Method31 was used to extract the 9 articles into a spreadsheet with the following headings: author(s), article title/journal, adverse effects related to IL-2 administration, definition of concepts, measures, sample, methods, strengths/weaknesses, findings, and suggested areas of future research. A synthesis of each symptom experienced by patients receiving IL-2 is presented by characteristic, severity, and prevalence.

Many of the cognitive adverse effects reported in this literature review were graded on toxicity. The term “toxicity” refers to the level of adverse effect severity and is graded by the NCI Common Terminology Criteria for Adverse Events scale.32 The NCI grades symptom severity on a scale of 1 to 5: grade 1 represents “mild” adverse effects, grade 2 represents “moderate” requiring intervention, grade 3 represents “severe” requiring medical treatment, grade 4 represents “life-threatening” adverse effects resulting in hospitalization or hospice care, and grade 5 represents “death.”32

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This section begins with an overview of patient demographics, attrition, and prior treatments reported in empirical articles, followed by an overview of cognitive and affective symptoms experienced by patients receiving high-dose IL-2 therapy. Results associated with cognitive symptoms are shown in Table 2. Table 3 provides detail on each article.

Table 2

Table 2

Table 3

Table 3

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Demographics, Attrition, and Treatment

The median ages of patients enrolled in the high-dose IL-2 studies ranged from 42 to 52 years, with the youngest reported age of 18 years and oldest reported age of 74 years. Large attrition rates were seen in patients receiving high-dose IL-2; only a small fraction of the population was able to receive all 4 cycles of IL-2 therapy. Attrition rates reported were as follows: 7% to 58% of patients stopped treatment after cycle 1, 29% to 52% after cycle 2, 3% to 20% after cycle 3, and only 3% to 35% of patients completed the maximum 4 cycles of high-dose IL-2. One study reported the reasons for attrition as patient’s choice, major depression, brain metastases/disease progression, or cardiac event.26 Patients received reevaluation scans after cycle 2 of high-dose IL-2 therapy, which might explain the high attrition rate after this cycle. Patients who had disease progression (development of brain metastases or development of additional lesions) were ineligible to receive additional cycles of IL-2. Interleukin 2 therapy is contraindicated for patients with brain metastases because increased fluid in the brain is thought to place patients at a higher risk of brain lesion hemorrhage due to the increase in intracranial pressure.33

Six articles reported the treatments that patients received prior to high-dose IL-2 therapy.1,15,17,22,24,26 Of these 6 studies, 2 studies enrolled only RCC patients,1,22 2 studies enrolled only melanoma patients,15,24 and 2 studies enrolled both melanoma and RCC patients.17,26Table 4 shows the treatments that melanoma and RCC patients received prior to high-dose IL-2 therapy. More than 75% of patients diagnosed with RCC had a nephrectomy. Nearly all patients with melanoma had surgery prior to treatment. Furthermore, many patients had multiple treatments prior to IL-2 therapy, including chemotherapy, previous immunotherapy, hormone therapy, radiation, and/or surgery.

Table 4

Table 4

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Cognitive Symptoms

Alterations in cognition, which include a wide array of symptoms, such as lethargy, confusion, inability to focus, and sleep insufficiency, are among the most challenging IL-2 adverse effects for patients and family members to experience and for providers to manage.5,6,34Cognitive fatigue” is a phrase encompassing the cognitive symptoms of IL-2, such as the symptoms listed previously in addition to confusion, decreased memory, and decreased attention span. The exact etiology of IL-2–induced cognitive alterations has yet to be determined. There are 2 theories related to altered cognition in patients receiving high-dose IL-2 therapy: (1) changes in brain matter (white and grey matter) in chemotherapy patients34 might be similar in IL-2 patients because IL-2 crosses the blood-brain barrier, and (2) alterations in cognition are related to fluid overload in the brain or cerebral edema, creating alterations in brain functioning,5 possibly related to capillary leak syndrome.

Fyfe and colleagues1 found that approximately 80% of patients experienced alterations in mental status, with more than one-fourth of IL-2 patients experiencing moderate to severe cognitive alterations. Approximately a third of IL-2 patients experienced confusion15,22,35 or severe neurotoxicity.22 Seizures in IL-2 patients are rare, although it is not clear if seizures that have been reported are related to a previous history of seizures or the development of brain metastases.1,22

It is difficult to determine what percentage of IL-2 patients are predisposed to cognitive alterations; however, cognitive fatigue impacts nearly 80% of patients receiving IL-2.1 Fortunately, grades 3 and 4 cognitive adverse effects impact slightly less than 25% of IL-2 patients.1 The low percentage of reported grades 3 and 4 cognitive adverse effects might be because patients who experienced severe symptoms removed themselves from therapy prior to receiving the full course of treatment.

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Affective Symptoms

Affective symptoms, such as mood alterations, depression, anxiety, aggression, hallucinations, and coma are difficult for patients and family members to adapt to.5,6,34 Gitlitz and colleagues22 reported that nearly 35% of IL-2 patients experience “hallucinations or significant neurotoxicity,” but we do not know the severity, or which affective symptoms the research team defined as neurotoxic. The symptom of depression has been reported; however, descriptions of other affective symptoms were found only on patient list-serves designed to allow patients and their family members to discuss their disease and treatments over the Internet.36 Musselman and colleagues26 measured depression with the Hamilton Depression Scale, whereas Capuron and colleagues23 used the Montgomery-Åsberg Depression Rating Scale to assess for depression. The 21-item Hamilton Depression Scale rates scores 0 to 6 as “normal,” 7 to 17 as “mild” depression, 18 to 24 as “moderate” depression, and scores equal to or greater than 25 as “severe” depression.37 The 10-item Montgomery-Åsberg Depression Rating Scale grades scores less than 10 as “normal” and scores greater than 30 as “severe” depression.38 Both scales measure various dimensions of depressive symptoms, but these researchers did not report other affective symptoms described by patients and families, such as anxiety and hallucinations.

Musselman and colleagues26 conducted a randomized controlled trial where they sought to determine if the prophylactic use of escitalopram, a selective serotonin reuptake inhibitor, reduced the level of depression in patients receiving the intervention drug. They measured depression over consecutive cycles of IL-2 and reported a significant increase in depression with each cycle, reaching a maximum level of depression in cycle 3. Mean scores on the Hamilton Depression Scale increased by 10 points.26 Capuron and colleagues23 measured depression at baseline, 1 week, and 1 month after IL-2 therapy and found an increase in depression scores at 1 week after therapy, with a significant increase at the 1-month time point.

The etiology of changes in affective symptoms from IL-2, such as depression, mood swings, fear, and tearfulness, is unknown; however, proinflammatory cytokines that are associated with mood regulation, such as adrenocorticotropic hormone, cortisol levels, and IL-6, are theorized to be a contributing factor to depression levels.26 It is hypothesized that cytokine-induced depression might be related to a disruption in the metabolism of serotonin,23 a neurotransmitter associated with mood stability and quality sleep.39 Tryptophan is an essential amino acid precursor necessary for the synthesis of serotonin.39 Capuron and colleagues23 found that a decrease in peripheral serum tryptophan levels was significantly associated with decreased appetite, pessimistic thoughts, suicide ideation, and decreased concentration. Because tryptophan is not produced by the body, it must be acquired through food,39 potentially contributing to a depression cycle related to loss of appetite and inevitably lower tryptophan levels.23

In summary, 2 studies measured depression,23,26 and 1 study reported hallucinations.22 Hallucinations were reported with signs of severe neurotoxicity; therefore, we were unable to distinguish the percentage of patients who experienced hallucinations as opposed to other affective symptoms. Reports and descriptions of other affective symptoms have been neglected in the peer-reviewed literature thus far. The few studies measuring affective symptoms in the high-dose IL-2 population were underpowered. Sample sizes for studies were 20 participants26 and 16 participants,23 respectively.

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Limitation of Existing Evidence

Within the reviewed literature, there was a wide array of studies varying in sample size, research design, reliability, and validity. Table 3 depicts an analysis of study methods for each article used for this review. Of the 9 articles, 7 contained empirical data,1,15,17,22–24,26 whereas 2 contained general information about IL-2 for patients, families, and providers,6,8 giving insight into known adverse effects and their clinical management. Of the 7 empirical studies, 5 used prospective methods,17,22–24,26 and 2 used retrospective methods.1,15 Studies were conducted in as few as 1 site and as many as 22 research centers (multicenter research). Sample sizes ranged from 16 to 283 participants. Five of the studies used the NCI toxicity scale for rating cognitive symptom severity,1,15,17,22,24 whereas the 2 studies describing affective symptoms used depression scales to report symptom severity.23,26

Although studies reporting cognitive symptoms enrolled between 124 and 283 participants, internal reliability was low because of the varying treatment centers and treatment protocols, particularly in retrospective studies. Only 2 studies evaluated affective symptoms, and sample sizes for these studies were small, ranging from 16 to 20 participants.23,26 There was a lack of standardization when assessing and screening for cognitive and affective symptoms in the high-dose IL-2 population. There appears to be a lack of consistency in the way cognitive/affective symptoms were reported, leading us to believe that each clinical facility may screen differently for cognitive/affective symptoms. Without an understanding of cognitive/affective symptoms and how they change over time in patients receiving IL-2 therapy, providers cannot know which symptoms to screen for, and the times at which screening should occur.

The lack of standardization in screening protocols may result in many symptoms being overlooked, underreported, and poorly managed. Although patients and families report sleep insufficiency as a primary concern, and researchers hypothesize that cytokines are associated with sleep disturbance, studies measuring sleep quality in the IL-2 population were not found.

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The only identified studies measuring pretreatment and posttreatment changes in IL-2 symptoms were conducted by Musselman and colleagues26 and Capuron and colleagues23; these studies measured depressive symptoms in IL-2 patients. Although researchers and clinicians reported many cognitive symptoms experienced by IL-2 patients,1,15,22,35 studies reporting cognitive symptoms did not document pretreatment levels of these symptoms. Standardized clinician-administered scales such as the Montreal Cognitive Assessment40 and the Mini Mental Status Examination26,41 are widely used to assess for cognitive alterations in the cancer population when neuropsychological testing is time and cost prohibitive; these scales were not used in these studies. Therefore, it is difficult to determine which IL-2 patients had baseline alterations in cognition resulting from prior treatment versus patients who experienced alterations in cognition as a result of IL-2 treatment.

Interestingly, Musselman and colleagues26 were the only researchers to use the Mini Mental Status Examination as a screening tool for IL-2 patient eligibility. Other researchers used the Eastern Cooperative Oncology Group performance status scores to evaluate patient eligibility for IL-2 but did not use a tool specific to cognition to measure the level of change in these symptoms.1,15,22,24

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The etiology of cognitive and affective symptoms is unclear and may be difficult to explore because of the complicated clinical course of cancer patients. Capillary leak syndrome, which is a life-threatening adverse effect experienced by nearly all patients receiving intravenous IL-2, causes increased vascular permeability, leading to fluid shifting out of the circulatory system and into surrounding tissue, exacerbating other negative adverse effects of IL-2,6 including cognitive and affective symptoms.42

Another plausible etiology as seen in patients receiving chemotherapy is decreased and damaged white and gray matter; however, studies have not been conducted on brain matter in patients receiving immunotherapy.43 Alterations in brain matter may possibly lead to cognitive fatigue and cognitive/affective symptoms because IL-2 crosses the blood-brain barrier; however, some researchers lean more toward the theory that alterations in cognition and affect are related to fluid overload in the brain or cerebral edema, creating changes in brain functioning.5 Perhaps these alterations are more severe and acute in IL-2 patients than in chemotherapy patients.

Patients and family members have reported cognitive/affective symptoms to be the most alarming and difficult symptoms related to high-dose IL-2 treatment. For example, a family member described challenges of these adverse effects through her parent’s IL-2 experience:

The second one was brutal. [Parent] could take 8 doses, but the mental adverse effects were more severe because her brain became very swollen. This time, she did not know where she was, who I was, or what was going on. She could not fall asleep for 24 hours, hallucinating all the time that she was in a mental institution and that people were trying to take her place. Then, they gave her something for anxiety, and she fell asleep, waking up only to go to the bathroom. Each time she woke up for the bathroom, she fought with me because she thought that the bathroom was not where I was leading her.44

Many patients agree that these symptoms are not adequately screened for, and patients were not informed about these potential changes.9

Our review of the literature confirms a lack of standardization when assessing, reporting, and managing cognitive/affective symptoms. Longitudinal studies describing the trajectory of depression ended either with the completion of 4 cycles of IL-2 therapy26 or a month after IL-2 therapy finished.23 We were unable to locate studies describing the trajectory of cognitive symptoms. To our knowledge, a study describing the degree of neurotoxicity in relation to the number of IL-2 cycles received by the patient has not been conducted. Although patients and family members describe sleep insufficiency as problematic, studies have not been conducted to quantify this loss of sleep in IL-2 patients.

While our understanding of patient adverse effects related to IL-2 administration has substantially improved, many important questions remain unanswered. Perhaps the largest uncertainty is the trajectory of IL-2–induced cognitive/affective symptoms. Patients and families describe cognitive/affective alterations as worrisome and debilitating, yet little emphasis has been placed on describing these symptoms. Furthermore, studies cannot be found that address whether patients return to baseline functioning after cessation of IL-2 therapy.

Although our review suggests altered cognition is present in high-dose IL-2 patients, the trajectories, breadth, and depth of cognitive/affective symptoms have yet to be described. This is an essential step for the advancement of cognitive/affective symptom science in the IL-2 population. Despite intervention studies designed to address the psychosocial complications of IL-2, such as depression, mood swings, fear, and tearfulness,26 an understanding of the level of altered cognitive/affective symptoms experienced by IL-2 patients remains unclear. Without an in-depth, descriptive study elucidating the characteristics of the cognitive/affective symptoms experienced by IL-2 patients, family members and providers cannot know which symptoms to assess for inpatients undergoing high-dose IL-2 therapy. Furthermore, we cannot alleviate these symptoms without an understanding of what the cognitive/affective symptoms are, the degree to which they are experienced, and how these symptoms change over time with each consecutive cycle of IL-2 therapy. Future studies should focus on describing the trajectory of cognitive/affective symptoms in the high-dose IL-2 population. A mixed-method case study approach might be beneficial to describe the experiences of patients, care partners, and providers and provide insight into these symptoms, when they appear, and how they change over time.

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Implications for Practice

Nurses and family members are the first line of defense when assessing for acute changes in cognition and affect, and the importance of their roles should not be minimized. It is important to reassure patients and family members that alterations in cognition and affect are prevalent and expected, and efforts should focus on techniques such as relaxation and reorienting the patient when needed.6 Enlisting the help of social workers, and engaging family members in techniques to maintain patient safety during times of anxiety and confusion might also be beneficial.6 Cognitive/affective alterations in high-dose IL-2 are multifaceted, meaning that these alterations might be the result of any or all of these factors: fluid overload, IL-2 crossing the blood-brain barrier, or the many concomitant medications used to reduce other severe adverse effects of IL-2 treatment.33 In addition to keen assessment skills, nurses should also determine if there are any PRN (pro re nata) medications that might be contributing to or exacerbating these alterations, for example, the use of lorazepam to assist with sleep and anxiety.

High-dose IL-2 is shown to have a plasma distribution of 13 minutes, and a plasma half-life of 85 minutes following a 5-minute bolus infusion,45 which might explain why most adverse effects are transient, peaking within 2 to 4 hours after the bolus IL-2 infusion. Educating patients and family members on potential cognitive/affective alterations is essential. Education about the illness trajectory and what to expect during and after treatment has been shown to help care partners and patients set realistic shared expectations, increase coping, and decrease feelings of powerlessness in the cancer population.46,47 Although most research focuses on patient interventions, care partner interventions have been found to help not only the care partner but also the patient in decreasing negative outcomes such as depression, anxiety, and distress.48,49

Nurses should institute the help of family members in assessing for acute cognitive/affective alterations, which might prove to reduce the anxiety of family members while improving outcomes for the patient. Finally, the trajectories, breadth, and depth of cognitive/affective symptoms have yet to be described, which is an essential for the advancement of cognitive/affective symptom science in the IL-2 population.

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Affective; Cognitive; Interleukin 2; Melanoma; Renal cell carcinoma; Symptoms

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