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• To compare the energy intake of patients receiving a normal diet and patients receiving TPN during interleukin-2 (IL-2) treatment and to establish whether total parenteral nutrition (TPN) is useful in improving nitrogen balance.
• To investigate the effect of TPN on biochemical abnormalities typically seen during IL-2 therapy.

• Metastatic or unresectable melanoma or renal cell cancer
• Pathologic confirmation of tumor histology
• Measurable disease
• Patients received high-dose IL-2 therapy via intravenous bolus
• Karnofsky performance status of >70%
• Normal stress multiple uptake gated acquisition or thallium scans
• Normal pulmonary, bone marrow, renal and liver function
• Patients from the General Clinical Research Center of the University of Utah Medical Center
• Informed consent was obtained from all patients participating in these studies.

• Pregnancy
• Active infection (including HIV)
• Steroid therapy
• Prior IL-2 therapy
• Organ allografts
• Brain metastases
• Prior malignancies
• No concurrent antineoplastic therapy was permitted.

Recruitment

• Sequential patients with metastatic or unresectable melanoma or renal cell carcinoma who received high-dose intravenous bolus IL-2 therapy in the General Clinical Research Center (GCRC) of the University of Utah Medical Center were used in this retrospective cohort analysis. 39 charts were reviewed with data from 37 patients evaluated for this study: 21 in the control group and 16 in the group who received TPN. The study was approved by the University of Utah Institutional Review Board. 

Design

• Retrospective cohort analysis. The first cohort of 21 patients received a normal diet during IL-2 therapy. The second cohort of 16 patients received TPN during IL-2 therapy.

Intervention

• TPN included a 1:1 admixture of a standard crystalline amino acid solution of 8.5% with 50% dextrose at 80-100 ml/h, depending on the estimated caloric needs of each patient. Caloric need were estimated using 30 kcal/kg body weight. Ideal body weight was used if the patient had a body mass index of ≥30. Each liter of TPN was supplemented with a standard electrolyte solution. One bottle of TPN each day was supplemented with multivitamins and trace minerals. Twice a week, patients received 250 ml of 10% intravenous fat emulsion.

• The control group received continuous intravenous infusions of D5/0.45NS, with 20mEq KCl added at 100-150 ml/h. Exogenous supplementation of potassium, magnesium and calcium was administered to both groups as required, based on lab changes.

Statistical Analysis

• T-test was used when clinical and demographic characteristics of both groups were compared
• X2-test for categorical variables
• A repeated measures analysis of variance was performed to determine whether the TPN significantly modified IL-2-induced changes in 11 laboratory values during the first seven days of IL-2 treatment
• Fisher's exact test was performed to compare the proportions of patients with abnormal test results in the TPN and the control groups on days one, five, and seven
  
• Time to progression and survival were calculated from the beginning of IL-2 treatment using Kaplan-Meier analysis 
  
• All analyses were performed using the Statistical Analysis System
• Significance was considered at P=0.0167 to control for a 5% type 1 error rate.

Timing of Measurements

Only data for the first seven days of treatment protocol were analyzed in the current study, since patients received almost all scheduled doses of IL-2 during this interval (mean number of doses, 12±2 of 14 planned doses in the TPN and control groups).

Daily measurements:

• Laboratory testing
• Complete blood count
• Electrolytes
• BUN
• Serum creatinine
• Glucose 
• Calorie counts for calorie and protein intake, analyzed by the Nutrition Care Services staff and the GCRC nursing staff. Patients were allowed to eat as tolerated. The American Diabetic Exchange List was used to estimate the amount of oral calories and protein consumed and daily protein and energy requirements were estimated.

Every-other-day assessments:

• A multiphasic chemistry screen (SMA 20) including a panel for liver function, calcium, phosphorus and cholesterol.

Pretreatment and posttreatment assessments:

• Measurement of tumor size for evaluation of clinical response
• Survival or relapse-free evaluations.

Dependent Variables

• Protein intake 
• Caloric intake 
• Potassium
• Calcium
• Carbon Dioxide
• Magnesium
• Albumin
• BUN
• Total bilirubin
• Direct bilirubin
• Phosphorus
• Glucose
• Creatinine.

Independent Variables

• TPN or normal diet.

Control Variables

• High dose intravenous bolus IL-2 treatment.

Initial N

• 39 patients.

Attrition (final N)

• 37 patients

• TPN: 16 (six women, 10 men)

• Control: 21 (14 women, seven men).

Age

• TPN: 46±12 years

• Control: 45±15 years.

Ethnicity

• Not specified.

Other relevant demographics

• None

• No significant differences between groups, except the greater proportion of women in the control group.

Treatment

• The IL-2 treatment regimen consisted of 600,000 IU IL-2/kg every eight hours on Days One through Five (priming course). A second identical course of IL-2 was administered on Days 11 through 15. Doses of IL-2 were skipped for NCI Common Toxicity Criteria grade III-IV toxicity (generally hypotension, renal dysfunction, pulmonary or neurologic toxicity). Some patients also received LAK cells on Days 11 through 15.

• To avoid differences in groups (LAK or not and differences in group size secondary to toxicity), only data from the first seven days was used in this analysis.

• All patients received 650mg of acetaminophen every four hours, 25 to 50 mg of indomethacin every eight hours and 150 mg of ranitidine every 12 hours as premedications as well as hydroxyzine and intravenous meperidine, as needed.

Anthropometrics

• Weight (kg)
• TPN: 70.6±14
• Control: 73.4±14.7.
• Height (cm)
• TPN: 171.5±7.6
• Control: 167.3±8.0.
• Percentage of Ideal Body Weight
• TPN: 105±21
• Control: 117±14.

Location

• The General Clinical Research Center (GCRC) of the University of Utah Medical Center.

Caloric intake During IL-2 Treatment

	TPN (Oral kcal/day)	TPN (Total kcal/day)	Control (Oral/total kcal/day)
Day One	483±514	1,782±828	178±434
Day Five	117±140	2,038±377	202±518
Day Seven	299±447	1,882±412	282±443

• Mean energy intake declined as early as the first 24 hours of IL-2 treatment and remained low throughout the experimental period.
• Control patients had a mean dietary intake of 2.5 kcal/kg (Day One) and 2.8 kcal/kg during the period of IL-2 administration (Day Five)
• Experimental group had an energy intake of 25 kcal/kg (Day One) and 29 kcal/kg (Day Five)
• Negative mean daily energy (-1,159 kcal/day over seven days) in controls, compared to estimated needs of 1,825±450 kcal/day, while the TPN group has a positive energy balance (+206 kcal/day over seven days) compared to 1,775±375 kcal daily requirement
• Protein nutrition was affected in a similar fashion, with patients receiving TPN having a greater protein intake than controls at Day One (1.02 vs. 0.12g/kg). Control patients had a mean dietary protein intake of 8±20 g/day (Day One), 6±17 g/day (Day Five) and 11±18 g/day (Day Seven). In contrast, patients receiving TPN had a protein intake of 72±33 g/day (Day One), 80±15 g/day (Day Five) and 78±21 g/day (Day Seven).
• Decrease in oral intake was found in both groups.

Protein intake During IL-2 Treatment

	TPN Oral g protein/day	TPN Total g protein/day	Control Oral/total g protein/day
Day One	22±27	72±33	8±20
Day Five	3±5	80±15	6±17
Day Seven	13±23	78±21	11±18

• TPN group had higher protein intake than controls (1.02 g/kg vs. 0.12 g/kg at Day One and 1.10 g/kg vs. 0.08 g/kg at Day Five)
• Negative protein (-47 g/day) balance in control patients compared a positive balance (+22 g/day) balance over the seven day analyzed period.

Weight changes

• There was no significant difference in maximal weight gain 5.6±2.4 vs. 4.9±2.2 kg) between TPN treated and control groups.

Survival

• No statistical difference between groups was noted in time to progression or in overall survival.

Biochemical analysis

• No significant difference between groups for all measurements at pretreatment
• Serum albumin dropped substantially in both groups following the onset of IL-2 treatment, but was not significantly different between groups at any timepoint. The decrease in serum albumin is a known consequence of IL-2 administration. The decrease in serum albumin was not altered by TPN administration.
• Serum calcium was significantly higher in TPN vs. controls on Days Five and Seven (P<0.01 and P<0.001, respectively), exact levels not provided
• On Day Five, 72% TPN group had WNL calcium levels vs. 29% controls (P<0.037)
• Control patients required at least 2 g calcium gluconate replacement, while TPN did not (P<0.0001)
• Serum potassium levels were not significantly different between groups during IL-2 treatment. However, on Day Seven, during diuresis seen in recovery, 32% of the controls developed hypokalemia, while none of the TPN group did, with the TPN group maintaining normal potassium levels (4.3 mmol/L), compared to 3.85 mmol/L seen in the controls (P<0.0006).
• Serum magnesium levels were also lower in controls (2.05 mg/dl), compared to TPN patients (2.31 mg/dl) (significance not provided) during recovery, despite magnesium supplementation in both groups.
• BUN and creatinine were higher in the TPN group, but did not impact renal recovery. Differences in BUN were not statistically significant between groups at any timepoint. Creatinine was higher on Day Seven (P<0.001). Exact values not provided. 
• Serum phosphorus dropped in both group, as suspected from IL-2 treatment. On Day Five, however, phosphorus was significantly lower in the TPN group (1.66 mg/dl), compared to controls (2.51 mg/dl).
• As suspected, serum glucose levels were higher in the TPN group.

• Their analysis revealed that protein and oral intake were markedly depressed in patients receiving IL-2 therapy.
• Compared to RDA of 58 g/day protein, controls only consumed average 11 g/day protein.
• Compared to est needs of 1825 kcal/day, controls only consumed average of 266 kcal/day.
• Similar pattern for caloric and protein intake was observed for the 2nd part of IL-2 treatment (details not recorded in manuscript) leading the authors to conclude that p.o. intake alone for a 2-3 week treatment period during IL-2 treatment is not adequate to prevent protein/calorie malnutrition.
• Nutrition was markedly improved over the period of IL-2 administration by TPN administration.
• They concluded that their study had demonstrated that TPN during high-dose intravenous IL-2 therapy provides short term benefit in overcoming severe protein and energy malnutrition induced by this treatment.
• As a result of the electrolyte replacement in the TPN group, less hypocalcemia during and following treatment and higher levels of magnesium and potassium during recovery was seen.
• TPN administration resulted in less incidence of cholestatic jaundice typically seen during IL-2 treatment. The authors feel that this may be a result of TPN improving hepatic glutathione synthesis which in turn caused improved hepatic function.
• TPN did not have an impact on survival.

Government:	NIH
University/Hospital:	University of Utah
Not-for-profit	0 Foundation associated with industry:

• The retrospective analysis is a limitation in itself. The authors could choose the best data to analyze for improved outcomes.
• Did not exclude for malabsorption disorders
• Evaluation of caloric and protein intake using diabetic exchange lists a bit unreliable
• No information on staging of disease for groups
• Small sample size
• Phosphorus decrease in TPN group could be a result of refeeding syndrome
• A larger randomized controlled trial is needed.