Nutritional status, gastrointestinal functioning and quality of life of patients with locally advanced pancreatic cancer

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Nutritional Status, Gastrointestinal Functioning and Quality

of Life of Patients with Locally Advanced Pancreatic Cancer

Author: Cynthia Potjes Project number: 2015212

Project sponsor: VU University Medical Center School: Amsterdam University of Applied Sciences

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Nutritional Status, Gastrointestinal Functioning and Quality

of Life in Patients with Locally Advanced Pancreatic Cancer

Author: Drs. Cynthia Lochtenberg – Potjes Student number: 500652813

Study sponsor: VU University Medical Center Practice supervisor 1: J.E. Witvliet MSc

Practice supervisor 2: Dr. M.A.E. de van der Schueren

School: Amsterdam University of Applied Sciences School supervisor: H. Öztürk MSc

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Acknowledgements

I would like to thank Jill Witvliet MSc, practice supervisor from the VUmc, for giving me the chance to work on this special, interesting study and guiding me throughout the whole study process by giving it structure. Her English research paper-writing tips and analytical skills were of great value to improve the article. Many thanks go to Dr. Marian de van der Schueren, study supervisor from the VUmc, who gave me the confidence to write this final thesis in an English article format, helped me not to lose the big picture and shared her valuable research paper-writing experience, all with great enthusiasm.

I am grateful to the guidance of Halime Öztürk MSc, school supervisor from the Amsterdam

University of Applied Sciences, whose fresh, ‘outsider’ view on the article prevented me from writing a piece of text not to be understood by anybody outside of the study project. Moreover, she helped me focus on the relevance of this study for the work of a dietician.

My thanks go to Nicolette Wierdsma MSc, research dietician at the VUmc, who was always ready to answer my questions on gastro-intestinal issues, and to Anne van der Werf BSc, medical researcher at the VUmc, for analyzing the CT-scans.

Last, but certainly not least, my greatest thanks go to the 16 brave patients in this study who endured all those tests, some of them stressful or with quite some impact. Thanks to their courage and determination to contribute to scientific research, future LAPC patients can benefit from an even more adequate treatment by dieticians and physicians.

Conflict of Interest Statement

The author of this article did not receive financial research support and declares to have no conflict of interest whatsoever.

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Abstract

Background & Aims: Although malnutrition is frequently described in patients with locally advanced

pancreatic cancer (LAPC), little quantitative data is available on the nutritional status, gastrointestinal functioning and quality of life of these patients.

Methods: Patients with LAPC included for experimental treatment by Irreversible Electroporation (IRE) were included. Weight loss in the past six months (kg), body mass index (BMI), nutritional intake (4-day diary), fat free mass index (FFMI), handgrip strength, resting energy expenditure by indirect calorimetry (REE) and gastro intestinal functioning measured by intestinal absorption capacity of energy and macronutrients (3-day feces collection and bomb calorimetry), exocrine pancreatic function by fecal elastase-1 (FE1), and quality of life (QoL) by the gastrointestinal quality of life index questionnaire, were measured before IRE.

Results: Sixteen patients (50% male; mean age 60.3 ±9.5 years) were included. Median weight loss over the past 6 months amounted 10.1 kg [IQR 4.8 – 14.3], mean BMI was 23.9 ± 2.5 kg/m2. Energy and protein intake were 27 ±10 kcal/kg and 1.0 [±0.4] g/kg respectively. The minimum reference value of 25 kcal/kg/day was met by 67% of the patients. In 7 patients the FFMI and in 8 patients the handgrip strength was <P10 of reference values. Median REE as % of predicted REE by the Harris & Benedict equation was 132% [IQR 114 – 142]. Malabsorption (<85%) of energy, fat and protein was observed in respectively 9 (range 21-96%), 8 (range 7-97%) and 12 (range 16-100%) patients. Median energy loss was 332 [IQR 205-1103] kcal/day. Exocrine pancreatic function was severely impaired (FE1 < 100 μg/g) in 11 patients. Total QoL was scored ‘ample satisfactory’ (71% of maximum score).

Conclusions: Despite an apparently sufficient nutritional intake, patients with LAPC have a severely impaired nutritional status, most likely as a result of an increased resting energy expenditure and decreased absorption capacity of energy and macronutrients. Individual differences are large. This requires a comprehensive assessment for each individual LAPC patient in order to provide adequate nutritional treatment.

Key words: Pancreatic cancer; nutritional status; REE; malabsorption; quality of life; gastrointestinal

Abbreviations

APPT = activated thromboplastin time BMI = body mass index

FE1 = fecal elastase 1 FFM = fat free mass FFMI = fat free mass index GI = gastrointestinal

GIQLI = gastrointestinal quality of life index HB’84 = Harris Benedict, 1984

INR = international normalized ratio IQR = interquartile range

IRE = irreversible electroporation

LAPC = locally advanced pancreatic cancer m = measured

NA = nutritional assessment p = predicted

QoL = quality of life

REE = resting energy expenditure SD = standard deviation

TEE = total energy expenditure VUmc = VU University Medical Center WHO’85 = World Health Organization, 1985

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1. Introduction

Pancreatic cancer, a disease with a 5-year survival rate of less than 5%, is one of the most aggressive carcinomas, with a mean age of patients at time of diagnosis of 63.1 (±11.1) years. Median survival time of patients with unresectable tumors is 12 – 15 months. In 2012, the number of patients diagnosed with pancreatic cancer worldwide was 337,872 (2.4% of all cancers1). The estimated mortality rate is 98% of the estimated incidence rate in one year (1-4).

Exocrine pancreatic carcinomas account for about 95% of the cases (5). Due to the generally late presentation of the disease, 80-85% of the patients diagnosed with exocrine pancreatic cancer has a locally advanced carcinoma (6), of which 50% are without evidence for metastases. Surgical

resection, the only potentially curative treatment, is not an option for this group (7,8). Pancreatic cancer has the 11th most common incidence rate of all cancers worldwide2, but as a result of late diagnosis and limited curable options, it is the fourth cause of cancer death (1,4,9).

It is known that a pancreatic carcinoma (resectable, locally advanced or metastatic) may affect the nutritional status, gastrointestinal (GI) functioning and quality of life (QoL). This is a result not only of exocrine insufficiency causing maldigestion and malabsorption, but also of metabolic changes causing an increased resting energy expenditure (REE) and reduced intake by anorexia, anxiety, nausea, early satiety, pain and depression (10-14). Improved nutritional status in cancer patients is positively related with quality of life (15,16). In patients with locally advanced pancreatic cancer (LAPC) without diagnosed metastases. However, little quantitative data is available about this homogeneous group of LAPC patients on all three of the aforementioned nutritional, GI functioning and QoL aspects, and the interactions between them. For this reason, this quantitative study describes a cross-sectional, comprehensive assessment of these aspects in patients with LAPC without evidence of distance metastases.

1_{Excluding non-melanoma skin cancer, GLOBOCAN 2012 (1).} 2

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2. Patients and Methods

2.1 Patients

Initially, 21 patients were selected for the PANFIRE study at the VU University Medical Center (VUmc), a study that investigates the safety of ‘Irreversible Electroporation’ (IRE) techniques in the pancreas. Between April 2014 and January 2015, 16 patients of the PANFIRE study also entered the PAN-NUTRIENT study, which focusses on the nutritional, GI functioning and QoL consequences of the IRE treatment. All patients were diagnosed with unresectable LAPC without diagnosed metastases. A multidisciplinary team of medical specialists of the VUmc judged the unresectability based on suggestions of the M.D. Anderson Cancer Center Pancreas Cancer Group (17) and the National Comprehensive Cancer Network (18). Detailed in- and exclusion criteria are described in attachment 1. No patient entered the comprehensive assessment within one month of surgical, endoscopic or chemo treatment. The Medical Ethics Review Committee of the VUmc approved the study and patients gave written informed consent for participation before entering.

2.2 Assessment

Before treatment with IRE, a dietician performed a comprehensive assessment on all 16 patients in an outpatient setting as part of a study that examines the nutrition related impact of IRE (PAN-NUTRIENT study), including a nutritional assessment (NA), assessment of GI function and QoL. This cross-sectional study describes the results of the comprehensive assessment in a quantitative manner.

2.2.1. Nutritional Assessment

The NA was performed as described below:

2.2.1.a. Body Mass Index and weight changes

To determine body mass index (BMI), height was measured with a stadiometer with the patient standing without shoes and determined to the nearest 0.5 cm. Weight was measured with the patient standing with light clothing and without shoes on a Seca scale, model 877 7021094 and determined to the nearest 0.1 kg. Weight changes were determined by self-reported historical weight measurements. Patients were considered malnourished if they had involuntary lost weight more than 10% in the past six months or more than 5% in the past month, or if they had a BMI <18.5 kg/m2 (<65 years of age), or <20 kg/m2 (≥ 65 years of age) (19-21).

2.2.1.b. Nutritional intake of energy and protein

Patients kept record of a 4-day food diary. A dietician had instructed the patients on use of the diary beforehand. Average daily intakes were computed with ‘Voeding’ (‘Nutrition’),a computer

application based on the Dutch food composition database (20). Energy-intake was compared to different prediction equations to predict energy requirements according to Harris Benedict, 1984 (HB’84) and World Health Organization, 1985 (WHO’85) equations (23,24). Protein intake was compared to a minimum requirement of 1.2 g/kg/day, conform the reference for cancer patients (25).

2.2.1.c. Fat Free Mass Index

Body composition was measured by bio-electrical impedance analyses using a Bodystat© 1500MDD. Patients were asked if they retained extra fluid in their body. Patients with a fat free mass index (FFMI) below the P10 of Schutz et al. (26) were classified as being malnourished.

2.2.1.d. Resting Energy Expenditure

Since only half of the predictive REE equations for patients is estimated within 10% of the measured REE (mREE), and thus rather inaccurate (27), REE of the patients was computed by indirect

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ventilated hood system, metabolical monitor(Vmax Encore n29, Viasys) and Weir’s equation (28) were used. Gas analyzing instruments were calibrated before measurements with two gas mixes as reference: a) 16% O2, 4% CO2, bal. N2 and b) 26% O2, bal. N2 (Viasys). Patients were in an outpatient setting in supine position for 30 minutes in rest, but without falling asleep. Patients with a 10% deviated mREE from the predicted REE (pREE) as calculated from the HB’84 or WHO’85 equations (23,24) were considered to have an in- or decreased REE. A mREE adjusted for fat free mass (FFM) below or above 1 SD of 30.3 [±4.1] kcal/kg/day, the reference of healthy controls by Cao, et al (2010) (29), was considered as a decreased or elevated REE. Total energy expenditure (TEE) was calculated by adding a fixed 30% activity factor to the REE, the recommended activity surplus for the large majority of patients (including physical activity and illness factor) (30).

2.2.1.e. Handgrip strength

Handgrip strength is a measure for functional muscle ability of patients in a clinical practice (31). Patients performed three consecutive handgrip strength tests with a Baseline hydraulic analogue hand dynamometer 120240 with the non-dominant hand. The average power in kg was used to obtain an indication of their peripheral muscle function (32). Patients with outcomes <P10 reference values of Bohannon et al. (2006) (33) were considered to be malnourished.

2.2.1.f. Fat-soluble vitamin status

Blood samples of vitamin A, D (25-OH), E (tocoferol), and the derivatives of vitamin K: International Normalized Ratio (INR) and activated partial thromboplastin time (APPT) values were taken by trained medics to evaluate possible deficiencies in fat-soluble vitamins. Normal serum values used at the VUmc are respectively: 1.2 – 3 μmol/L, >50 nmol/L, 20 – 39 μmol/L, and 0.80 – 1.20 INR and APPT. Patients with values under these norms were considered to have a vitamin deficiency. 2.2.2. Assessment of gastrointestinal function

Gastro-intestinal function of the patients was determined by small intestine absorption capacity. Bomb calorimetry, the gold standard for intestinal absorption testing, was used (34). Exocrine function of the pancreas was quantified by fecal elastase-1.

2.2.2.a. Absorption capacity testing by food-intake and bomb calorimetry

To measure the small intestine absorption capacity, the difference in food intake and fecal loss as percentage of the daily macronutrient energy intake was calculated. Patients were instructed to stop using pancreatic enzymes two days before the start of feces collection. Daily food intake was

recorded in and computed from the 4-day food diary, as described under paragraph 2.2.1.b. Patients started the diary one day before the start of feces collection, because practice based experience shows a much faster average gastro-intestinal transit time in patients with a pancreatic carcinoma who do not use pancreatic enzymes than the 33 – 60 hours in healthy adults (35). Therefore, the average daily energy, protein, fat and carbohydrate intake of four days were needed to use for calculations with the average daily fecal energy losses from three days. Patients saved the collected feces until use <4°C in a previously weighed bucket. The central laboratory of the University Medical Center Groningen performed the bomb calorimetry (34,36) with a portion dry feces and the

Gallenkamp ballistic bomb calorimeter (type CB-330). The average 3-day fat losses were determined with the ‘Van der Kamer’ method (37). Average protein loss was estimated by nitrogen

determination in the feces according to the ‘Kjelhdal’ technique (38), using 6.25 as multiplier to calculate protein loss. Carbohydrate loss was calculated from the difference between the average daily energy losses and the average daily fat- and protein losses in kcal according to the Southgate calorie conversion factors (39). An energy, fat, protein or carbohydrate absorption capacity of 75 - 85% was defined as moderate malabsorption and <75% as severe malabsorption (33,40). Energy losses of >200 kcal/day were classified as malabsorption (34).

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2.2.2.b. Exocrine pancreatic function testing by fecal elastase-1

Exocrine pancreatic function was determined by fecal elastase-1 (FE1) test. The FE1 test has proven to be a highly sensitive pancreatic function test. FE1 is a specific human protease synthesized by the acinar cells of the pancreas. It is stable during transit and unaffected by exogenous pancreatic enzyme treatment, so its detection in the stool is uncomplicated (41). Fecal elastase-1 (FE1) was determined from a sample feces used for the bomb calorimetry. The results of FE1 were presented in μg/g stool. FE1 <15 μg/g could not exactly be determined. Exocrine pancreatic function was defined as “reduced" (100 – 200 μg/g), and "severely reduced" (≤100 μg/g) (41).

2.2.2.c. Self-reported observations of stool

In case patients clinically reported on steatorrhea-related terms like “sticky,” “floating” and/or “fat” a correlation between these patient reports and fat absorption in percentage, as determined by the bomb calorimetry and food diary analysis, was checked.

2.2.3. Quality of Life assessment

QoL was objectified by the Gastro Intestinal Quality of Life Index (GIQLI) questionnaire. The questionnaire assesses health-related quality of life of patients with GI disease and has been validated in The Netherlands for patients with potentially operable periampullary carcinoma (42). Questions were scored on a 5-point scale with the least desirable answer scoring 0 and the most 4. Maximum total score was 144. Results were divided into four subscales: physical well-being, mental well-being, digestion and defecation (42). Patients filled out the test at home in the days before the assessment, during the 4-day food diary reporting and feces collection. Only fully answered

questionnaires were used for total/total item mean score analysis, and only fully answered subscales were used for subscale analyses. Mean sums as a percentage of maximum score of <55 were

considered ‘unsatisfactory,’ ≥55 – 70 ‘satisfactory,’ ≥70 – 80 ‘ample satisfactory,’ and ≥80 ‘very satisfactory’.

2.3. Statistics

Normally distributed variables were described as mean and standard deviation (SD). Not normally distributed variables were described as median and inter quartile ranges (IQR). The Wilcoxon signed-ranks test was used to determine significance between not normally distributed paired variables . To determine a correlation between not normally distributed variables, Spearman’s rho test was used. Strength of correlations were expressed in “very weak (0.00 – 0.19),” “weak (0.20 – 0.39),”

“moderate (0.40 – 0.59),” “strong (0.60 – 0.79)” and “very strong (0.80 – 1.0)” according to Evans’ (1996) classification for the absolute value of rs (43). P <0.05 was considered to be significant. All data were documented (attachment 2) and analyzed in SPSS version 18.

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3. Results

3.1. Patients

Descriptive statistics of personal and clinical characteristics of the enrolled patients at the time of assessment are summarized in Table 1. Time lapse since diagnosis of pancreatic carcinoma was 1 – 16 months.

Table 1: Baseline personal and clinical characteristics of the patient group

Patients N=16

Male / Female, n 8 / 8

Mean age, years [SD] 60.3 [9.5]

Tumor location, n1 15

Head 10

Tail 1

Uncinate process 4

Patients with previous treatment2, n 14

Patients with pancreatic enzyme replacement therapy3, n 7

Patients with dietician in consult4, n 10

1

N=15: After the comprehensive assessment had taken place one patient disenrolled from the PANFIRE study because IRE treatment was cancelled, resulting in missing medical data on tumor location.

2_{Previous treatment being: chemo (3), percutaneous transhepatic cholangiography drain or plastic endoprothese (3), chemo and drain (2),} gastrojejunostomy (1), hepaticojejunostomy (2), hepaticojejeunostomy and chemo (1), double bypass (1), double bypass and chemo (1). 3

Patients commenced enzyme treatment varying from two months to three weeks before the assessment. 4 _{Patients received counseling from a dietician varying from two months to ten days before the assessment.}

3.2. Nutritional Assessment

All measurements were performed by standardized operating procedures wherever possible. Results of the NA are described below. Additional results and reference values are shown in Table 2.

3.2.1. Body Mass Index and weight changes

All patients had a BMI above 18.5 kg/m2. Two out of 14 had not lost weight and none of the patients had lost >5% of their body weight in the past month. Ten out of 14 patients were defined as

malnourished based on involuntary loss of more than 10% of their bodyweight in the past six months with a median weight loss of 10.1 [4.8 – 14.3] kg.

3.2.2. Nutritional intake of energy and protein

When comparing nutritional intake to the requirements calculated by estimations, average median daily energy intake was insufficient in four (HB’84) respectively seven (WHO’85) out of 15 patients. Protein intake averaged 1.0 g/kg/day and was insufficient (<1.2 g/kg/day) in 11 out of 15 patients. As is shown in Table 2, the difference between the daily intake in kcal/day and the mTEE is significant, whereas the difference between the daily intake and the pTEE (HB’84 as well as WHO’85) is not. 3.2.2. Fat Free Mass Index

None of the patients subjectively retained extra fluid. Seven patients demonstrated a FFMI below the 10th percentile of their reference values. FMI was normal for all patients.

3.2.3. Resting Energy Expenditure

In 12 out of 15 patients the mREE was >10% higher than the pREE of either HB’84 or WHO’85. Median mREE was significantly higher than pREE: 634 [252 – 733] kcal/day higher compared to the HB’84 and 590 [276 – 736] kcal/day higher compared to the WHO’85 equation. Median mREE expressed in kcal/kg/day was 30% higher than the median pREE in kcal/kg/day computed with the pREE’s of the HB’84 and WHO’85 equations. mTEE in kcal/day was significantly higher than energy intake and 10 out of 15 patients were not able to reach an intake conform or above their mTEE. The pTEE’s of HB’84 and WHO’85 were not significantly higher than energy intake in kcal/day.

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10 3.2.4. Handgrip strength

Half of the men and women performed below the 10th percentile of grip strength reference values. 3.2.5. Fat-soluble vitamin status

None of the patients had used vitamin A, D, E or K supplements . Two patients showed a vitamin A, nine a vitamin D 25-OH and two a vitamin E deficiency. None of the patients had a INR or APPT time below the reference. There was a strong positive correlation between fat absorption capacity (%) and vitamin D 25-OH in blood serum (rs = 0.60, p = 0.009). No other correlations between fat absorption capacity and the investigated blood serum values were found.

Table 2: Results of the nutritional assessment

Nutritional Assessment1 _{Median [IQR]} _Mean

[SD]

Reference value

p BMI and weight changes

BMI (kg/m2) 23.9 [2.5] 18.5 – 24.99

Weight loss past six months2_(%) _{13 [6 – 17]} _{< 10}

Intake3 [IQR]

Energy intake (kcal/day) 1926 [1681 – 2283] †

mTEE: 2378 [2109 – 2793] † pTEEHB’84: 1773 [1674 – 1927] pTEE WHO’85: 1786 [1730 – 1885] 0.047 0.331 0.363

Energy intake (kcal/kg/day) 27 [10] 25 – 30

Protein intake (g/kg/day) 1.0 [0.4] 1.2 – 1.5

Body composition, M and F

FFM (kg) M: 54.0 [49.8 – 58.0]

F: 41.0 [38.3 – 43.8]

47.8 – 52.4 35.7 – 37.9

(m/p)REE and (m/p)TEE4

REE (kcal/day) mREE: 1829 [1622 – 2030]† pREE HB’84: 1357 [1281 – 1469] †

pREE WHO’85: 1372 [1316 – 1440] †

0.001 0.002

REE (kcal/kg/day) mREE 26.0 [22.4 – 28.0]† pREE HB’84: 20 [19 – 20] †

pREE WHO’85: 20 [18 – 22] † 0.001 0.002 mREE/pREE (%) pREE HB’84: 132 [114 – 142] † pREE WHO’85: 133 [115 – 147] † 100† 0.001 0.002

REE/FFM (kcal/kg FFM/day) mREE: 35 [33 – 43] † pREE HB’84: 30 [26 – 32] †

pREE WHO’85: 29 [26 – 35] †

0.001 0.002

TEE (kcal/day) mTEE: 2378 [2109 – 2639] † pTEE HB’84: 1773 [1674 – 1927] †

pTEE WHO’85: 1786 [1730 – 1885] †

0.001 0.002

mTEE – pTEE (kcal/day) pREE HB’84: ∆ 634 [252 – 733] †

pREE WHO’85: ∆ 590 [276 – 736] † ∆ Nil†

0.001 0.002

mTEE – energy intake (kcal/day) ∆ 423 [-298 – 776]† ∆ Nil† 0.047

Fat soluble vitamin status

Vitamin A (μmol/L) 2.1 [1.3 – 2.5] 1.2 - 3

Vitamin E (μmol/L) 25 [22 – 31] 20 - 39

Vitamin D 25-OH (nmol/L) 46 [34 – 70] ≥ 50

APPT (s) 34 [32 – 37] 25 - 40

INR (s) 1.03 [0.98 – 1.05] 0.90 – 1.10

1_{BMI = body mass index, IQR = inter quartile range, m = measured, p = predicted, TEE = total energy expenditure, HB’84 = Harris Benedict} equation, WHO’85 = World Health Organization equation, M = male, F = female, REE = resting energy expenditure, FFM = fat free mass, APPT = activated partial thromboplastin time, and INR = International Normalized Ratio.

2

N=14: Two persons could not recall their historical weight (pregnancy and unknown reason). 3

N=15: One patient could not start a food diary because of an emergency IRE treatment. † Significant difference between values with symbol in same row.

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3.3. Gastrointestinal function

Results of the assessment of the GI function are described below. Table 3 shows additional results and reference values wherever available.

3.3.1. Absorption capacity testing

Thirteen out of 15 patients had malabsorption of one or more macronutrients. Three patients stopped enzyme supplementation only one day before feces collection, but their results were all included in the analysis. Median energy loss was 332 [IQR 205-1103] kcal/day. Individual differences were evident: Forty percent of the patients did not display energy malabsorption, while another 40% displayed severe malabsorption. The remaining 20% showed moderate malabsorption.

3.3.2. Exocrine pancreatic function testing

Of four patients, FE1 values in the stool were <15 μg/g and could therefore not exactly be determined. In analyses 7.5 μg/g was used for those uncertain values. Figure 1 shows the strong, positive correlation that was found between FE1 values and energy absorption capacity in % (rs = 0.74, p = <0.001).

rs = 0.74

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12 3.3.3. Self-reported observations of stool

Out of ten patients who clinically reported fat in their stool, eight were diagnosed with fat malabsorption. Three patients reported no complaints related to malabsorption and indeed their energy and fat absorption capacity was above 85%. Fat absorption capacity and stool observations were moderately correlated (rs = -0.54, p = 0,029).

Table 3: Results of the assessment of the GI function

Assessment of GI function Median [IQR] Reference value1 Number of patients2 Energy absorption capacity (%) 82.9 [47.8 – 87.9]

≥ 85 75 - 85 < 75 6 3 6

Fat absorption capacity (%) 84.2 [39.1 – 93.0]

≥ 85 75 - 85 < 75 7 2 6

Protein absorption capacity (%) 77.0 [54.5 – 81.6]

≥ 85 75 – 85 < 75 3 6 6

Carbohydrate absorption capacity (%) 80.6 [62.7 – 85.0]

≥ 85 75 – 85 < 75 5 3 7

Energy losses (kcal/day) 332 [205 – 1103] ≤ 150 – 200 >200 3 12 FE13 (μg/g) 60 [<15 – 145] ≥ 200 100 – 200 <100 2 2 11

1_{Reference values for absorption capacity: ≥ 85% = normal absorption, 75 – 85% = moderate malabsorption, <75% = severe malabsorption.} Reference values for energy losses: ≤ 150 – 200 kcal/day = normal absorption, > 200 kcal/day = malabsorption. Reference values for FE1: ≥200 μg/g = normal, 100 – 200 μg/g = reduced, <100 = severely reduced pancreatic function.

2_{N=15: One patient did not collect feces because of logistical problems.} 3

FE1 = fecal elastase-1.

3.4. Quality of life

Table 4 presents the outcomes of the QoL assessment and shows that total score, as well as sub scores, all scored at least ‘satisfactory.’ In general, patients valued their QoL expressed in

gastrointestinal defecation the highest and mental well-being the lowest. As opposed to all other items, item 10 was scored 1 to 5 in the original questionnaire (instead of 0 – 4) and item 23 with 0 for the most and 4 for the least desirable answer (instead of 0 for the least and 4 for the most desirable). However, to guard homogeneity in scoring, those two items were scored in the same way as the other 34 items.

Table 4: Results of the QoL assessment

GIQLI Mean sum1 Score

range

Mean sum as % of maximum score

Mean item score2 No. of items Total3 102 [82.5 – 118.5] 0 – 144 71 2.83 [2.29 – 3.29] 36 Physical well-being4 25.5 [16.8 – 30.0] 0 – 40 65 2.55 [1.68 – 3.00] 10 Gastrointestinal digestion4 31 [20 – 34] 0 – 40 78 3.10 [2.00 – 3.40] 10 Gastrointestinal defecation4 20 [17.5 – 22] 0 – 24 83 3.33 [2.92 – 3.67] 6 Mental well-being3 12 [10 – 13.3] 0 – 20 60 2.40 [2.00 – 2.65] 5 1

Median of mean sum [IQR] 2

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N=12: Questionnaires of one patient who did not return the questionnaire, one patient who missed out on items 17 until 36, one WHO’85 missed out on item 13 and one on item 30 (all for unknown reasons) were left out from the analysis.

4

N=14: Questionnaires of one patient WHO’85 did not return the questionnaire and one patient WHO’85 missed out on items 17 until 36 (both for unknown reasons) were left out from the analysis.

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4. Discussion

This study suggests that patients with locally advanced pancreatic cancer without evidence of metastasis generally have a severely impaired nutritional status, most likely due to an insufficient gastrointestinal functioning and an increased energy expenditure. Despite an apparently sufficient energyintake according to the estimated requirements by equations, the intake was deficient when compared to measured energy expenditure. Protein intake was generally below requirements. Finally, a decreased absorption capacity of energy out of fat, protein and carbohydrates was observed in the majority of patients.

Nutritional assessment

Based on BMI, none of the patients would have qualified for an impaired nutritional status, although most of them had lost a considerable amount of body weight in the preceding six months. Therefore, BMI is possibly not an adequate parameter for nutritional status in LAPC patients. Impaired

nutritional status did become visible after inquiry about weight changes, examination of body composition and measurement of handgrip strength.

Abdominal CT scans, being part of the routine assessment of pancreatic tumor progression or regression, were initially used to determine the skeletal muscle index. However, these results were not included in this article, because the scans and assessments were never on the same day. Moreover, the time span between those two could mount to several months, resulting in outdated data.

The mREE expressed in kcal/day in this study was significantly higher compared to the pREE’s of the HB’84 and WHO’85 equations (33 and 32% respectively). Earlier studies demonstrated similar results of mREE in patients with pancreatic cancer (9,11,44,45). The lower mREE elevation in Moses et al, 2004 (9%) and Vaisman et al, 2012 (6.9%) compared to our study (33 and 32%), and the insignificance in the mREE/FFM ratio of the Vaisman et al, 2012 study could possibly be explained by the more cachectic patient groups in both studies that included metastasized patients as well, and the

comparison to the Schofield equation (having a higher pREE) in the Moses study. These patients have already lost more weight and lean tissue compared to patients in this study with a relatively high median FFM in kg, which possibly causes a lower mean FFM in kg in the Vaisman study.

As opposed to unintentional weight loss in the past month, unintentional weight loss in the past six months seemed to be a much better indicator of malnutrition in this study. This could be explained by the fact that the majority of the patients who had been losing weight had seen a dietician and/or had started to use enzyme supplementation in the month before the assessment.

Despite a severe fat malabsorption in the majority of patients in this study, deficiencies of the fat-soluble vitamins A, E and K were not found. Sufficient levels of vitamins A and E are expected, since they are stored in the body for months to years (46). This could explain sufficient vitamin A and E levels in the majority of patients. This study showed the strong positive correlation between vitamin D 25-OH and fat absorption capacity. On the other hand, the result of 56% of the patients having a vitamin D 25-OH deficiency, did not differ much from the 50% of the ‘independently living elderly’ in the Netherlands suffering from vitamin D 25-OH deficiency as well (47). Therefore, the deficiency in the patients of this study might as well be attributed to deficiency causes similar to those of the independently living elderly in the Netherlands, without having any relation to the impaired fat absorption.

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Gastrointestinal function

A striking fact in this study seems to be the worsened absorption capacity in 13 out of 15 patients of at least one of the macronutrients. The median absorption capacity expressed in percentages suggests malabsorption. However, individual differences in energy absorption capacity differed, with 40 % of patients having a normal energy absorption, as opposed to 20% moderate malabsorption and 40% with severe malabsorption. These individual differences could, in this study, be explained by neither location, nor size of the tumor. Searches in Pubmed, Science Direct and Google Scholar did not yield any other study on the absorption capacity of pancreatic cancer patients.

This study demonstrated a strong positive correlation between FE1 and energy absorption capacity, which suggests that the energy absorption capacity in this patient group seems to depend on the functionality of the exocrine function of the pancreas. Apparently, the FE1 test predicts absorption capacity of patients with LAPC well, making it a practical diagnostic tool to support the physician in the decision making process whether or not to subscribe enzyme supplements. In addition, patients seemed to be quite adequate in their observation reports of their own stool in relation to their fat absorption capacity. In only one patient the reported clinical symptoms, which suggested

malabsorption, did not comply with the results of the fat absorption capacity test. Patients without complaints did indeed have normal absorption. The study of Pongprasobchai (48) states that severe exocrine pancreatic insufficiency (fecal fat >15 g/day) can be easily diagnosed with clinical symptoms of steatorrhea, but that subclinical insufficiency is best diagnosed by, for example, a FE1 test. Sikkens et al. (49), suggests that patients with a pancreatic head tumor may have already suffered from exocrine insufficiency at the time of diagnosis and that the use of enzyme treatment prevents weight loss and improves QoL even though clinical symptoms of steatorrhea were not always present. D’Haese et al. (50) reported in the study on 294 chronically exocrine pancreatic insufficient patients that QoL improvement was noticeable at least within six months after commencement of pancreatic enzyme therapy.

Quality of life assessment

The patients in our study valued their present quality of life ‘ample satisfactory’. Patients even valued their gastrointestinal digestion and defecation respectively as ‘ample satisfactory’ and ‘very

satisfactory’ despite the clinically evident gastrointestinal impairments in the majority of patients (Table 4). Results were, however, not adjusted for any (previously received) surgical, enzyme and/or dietetic treatment. Patients scored lowest on ‘mental wellbeing’ which could possibly be explained by the likelihood of extreme emotional stress for cancer patients in the palliative stage. Nieveen – van Dijkum et al, 2000 (42) studied the QoL of 125 patients with potentially operable periampullary carcinoma. This study found gastrointestinal digestion and defecation to be the highest scoring categories as well. The potentially curable patients of this study valued their mental well-being as ‘ample satisfactory’. Further research on the effects of nutritional interventions on the QoL in LAPC patients is recommended.

Strengths and weaknesses

This study is the first of its kind to provide a comprehensive insight in nutritional status, GI functioning and QoL in LAPC patients all at once, plus the interaction between them. Searches in Pubmed, Science Direct and Google Scholar did not find other studies that measured macronutrient absorption capacity in pancreatic cancer patients or studies investigating fat-soluble blood serum vitamin status in LAPC patients. All other tests and measurements have been performed on patients in all, or different stages of pancreatic cancer, but never on LAPC patients alone. As this study is a cross-sectional study, no conclusions on cause and effect can be drawn. Moreover, the sample size was small, due to strict inclusion and exclusion criteria, and patients were diverse in previous surgical treatment, chemo-, dietetic and enzyme therapies, and time since diagnosis. Still, the majority of patients appeared to be in a poor nutritional status.

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5. Conclusion

The present study, which captures the nutritional status, GI functioning and QoL of LAPC patients, shows the necessity for dieticians to perform a comprehensive assessment to be able to diagnose and treat these patients adequately. First of all, BMI does not seem to be an adequate indicator of nutritional status. Second, nutritional intake seems sufficient if compared to energy requirement equations, but the latter are apparently inadequate for these patients and tend to underestimate their actual energy needs. Third, energy absorption capacity can be severely impaired, or not be impaired at all. On top of all, the large individual differences between patients makes standard treatment difficult and needs to be kept in mind when treating this nutritionally compromised group of patients.

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6. Case Report

To demonstrate the importance of a comprehensive assessments with LAPC patients to be able to treat them according to their clinical needs, the following patient is discussed.

Patient:

54 year old female patient with LAPC in the uncinated process and without evidence for metastasis.

Function and anatomic characteristics:

Weight: 66.6 kg; height 1.62 m; BMI: 25.4 kg/m2; weight loss 13,4 kg within last six months and 5 kg within last month; PTC drain; feces with clinical symptoms of fat malabsorption; defecation several times a day; dysgeusia; FE1 <15 μg/g stool.

Nutritional assessment:

Handgrip strength: 27 kg. FFMI: 16 kg/m2

Energy intake: 1729 kcal/day; protein intake: 1,2 g/kg/day or 80 g/day. Energy absorption 68%

Vitamin D 25-OH: 21 nmol/L

Nutritional requirements:

Energy requirements by pTEE: 1729 (HB’84) and 1825 (WHO’85), and 2426 kcal/day by mTEE; 1.2 – 1.5 g protein/kg bodyweight/day or 80 – 100 g/day.

Activities:

Work: 2 hours/day in health care and studying to become coach/organizer in the health care. Household chores, groceries, cooking.

Participation:

Hobby: acting (attends club once a week).

External factors:

Dietician consulted a month ago. Pancreatic enzyme replacement therapy 1 – 1 – 2 (40.000 lipase, 25.000 amylase and 1.600 protease units per capsule) and two nutritional supplements per day (600 kcal, 40 g protein), both since one month.

Personal factors

Divorced with two sons (one still living at home), whom she does not want to burden with her disease. Quit smoking seven years ago after 40 pack years. Claustrophobic. Knowledge about dietary energy and protein is moderate. History of dieting. In 2007 mamma carcinoma, and in 1996 abdominoplasty. Action oriented towards diet, but has difficulties with drinking the second nutritional supplement of the day. Experiences her QoL as “satisfactory,” but ‘mental well-being’ as “unsatisfactory”. Wants to stop losing weight before IRE procedure.

Dietetic diagnosis:

54 year old woman, with LAPC without evidence for metastasis. IRE procedure planned within two weeks. PTC drain. Medical history: mamma carcinoma (2007) and abdominoplasty (1996). Patient finds herself in a poor nutritional status, based on 17 and 7% weight loss in respectively six and one month(s) as a result of decreased intake by dysgeusia, an increased mREE with 33 or 40% compared to the pREE’s of WHO’85 or HB’84 respectively, and a severely impaired absorption capacity of 68% without use of pancreatic enzyme replacement therapy and severely reduced FE1. After one month of 1 – 1 – 2 enzyme replacement therapy, still clinical symptoms of malabsorption. Handgrip strength and FFMI within reference values. Intake conform pTEE, but <75% of mTEE, including two energy and protein enriched nutritional drinks a day. Patient has a vitamin D OH-25 blood serum deficit. Patient is in action phase of contemplation stages of change.

Main objective:

Improve nutritional status within one week by stopping weight loss within two days, and hand grip strength with 0,5 kg in one month and maintain FFMI.

Sub-objectives:

1. Increase energy intake within one day with 700 kcal to 2430 kcal/day and maintain protein intake.

2. Improve absorption capacity with ≥ 17% to 85% within one week by increasing use of pancreas enzyme replacement therapy. 3. Improve vitamin D 25-OH status with ≥ 29 nmol/L within one month.

Practical agreements with patient

A. Insert feeding tube the next day for overnight tube feeding of 700 kcal semi-elementary nutrition.

B. Immediate increase of pancreas enzyme dose with two capsules a day, to be taken with the two nutritional drinks. C. Immediate start with vitamin D supplementation of 10 μg/day.

D. Start physiotherapy two times per week. E. Evaluation in one week.

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Attachment 1, In- and exclusion criteria

In- and exclusion criteria are copied from the project proposal (project NL42888.029.13, version 3.0) of the VUmc Cancer Center Amsterdam “Nanoknife project”: PANFIRE – Pilot study: Non-thermal ablation using ‘Irreversible Electroporation (IRE) to treat locally advanced pancreatic carcinoma – a phase I clinical trial.

General inclusion criteria

Screening must be performed no longer than 2 weeks prior to study inclusion. Subjects are eligible if they meet the following criteria:

 Radiologic confirmation of LAPC by at least CT of chest and abdomen (with the upper abdomen scanned according to a dedicated 3mm slice multiphase pancreatic tumor protocol), performed maximum 2 weeks prior to the procedure;

 Maximum tumor diameter ≤ 5 cm;

 Histological or cytological confirmation of pancreatic adenocarcinoma;

 Age  18 years;

 ASA-classification 0 – 3

 Life expectancy of at least 12 weeks;

 Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to definite inclusion;

o Hemoglobin ≥ 5.6 mmol/L;

o Absolute neutrophil count (ANC) ≥ 1,500/mm3 ; o Platelet count ≥ 100*109

/l;

o Total bilirubin ≤ 1.5 times the upper limit of normal (ULN); o ALT and AST ≤ 2.5 x ULN;

o Serum creatinine ≤ 1.5 x ULN or a calculated creatinine clearance  50 ml/min; o Prothrombin time or INR < 1.5 x ULN;

o Activated partial thromboplastin time < 1.25 x ULN (therapeutic anticoagulation therapy is allowed if this treatment can be interrupted as judged by the treating physician);

 Written informed consent.

General exclusion criteria

Subjects who meet the following criteria at the time of screening will be excluded:

 Resectable pancreatic adenocarcinoma as discussed by our multidisciplinary hepatobiliary team;

 Extrapancreatic metastases;

 Successful down staging after (radio)chemotherapy from previous unresectable/borderline tumor to resectable tumor;

 Stage IV pancreatic carcinoma;

 History of epilepsy;

 History of cardiac disease:

o Congestive heart failure >NYHA class 2;

o Active Coronary Artery Disease (defined as myocardial infarction within 6 months prior to screening);

o Cardiac arrhythmias requiring anti-arrhythmic therapy or pacemaker (beta blockers for antihypertensive regimen are permitted);

 Uncontrolled hypertension. Blood pressure must be ≤160/95 mmHg at the time of screening on a stable antihypertensive regimen;

 Compromised liver function (e.g. signs of portal hypertension, INR > 1,5 without use of anticoagulants, ascites);

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 Uncontrolled infections (> grade 2 NCI-CTC version 3.0);

 Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment;

 Immunotherapy ≤ 6 weeks prior to the procedure;

 Chemotherapy ≤ 6 weeks prior to the procedure;

 Radiotherapy ≤ 6 weeks prior to the procedure;

 Concomitant use of anti-convulsive and anti-arrhythmic drugs (other than beta blockers used for antihypertensive);

 Allergy to contrast media;

 Any implanted stimulation device;

 Any implanted metal stent/device within the area of ablation that cannot be removed;

 Any condition that is unstable or that could jeopardize the safety of the subject and their compliance in the study;

Of note, patients with contra-indications for MRI will not be excluded from participation: in this case radiologic follow-up will consist of CT-scanning according to protocol.

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Attachment 2, Variables of dataset

3

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Nutritional status, gastrointestinal functioning and quality of life of patients with locally advanced pancreatic cancer

Nutritional Status, Gastrointestinal Functioning and Quality

of Life of Patients with Locally Advanced Pancreatic Cancer

Nutritional Status, Gastrointestinal Functioning and Quality

of Life in Patients with Locally Advanced Pancreatic Cancer

Acknowledgements

Conflict of Interest Statement

Abstract

Abbreviations

Contents

1. Introduction

2. Patients and Methods

2.1

Patients

2.2

Assessment

2.3. Statistics

3. Results

3.1. Patients

3.2. Nutritional Assessment

3.3. Gastrointestinal function

3.4. Quality of life

4. Discussion

Nutritional assessment

Gastrointestinal function

Quality of life assessment

Strengths and weaknesses

5. Conclusion

6. Case Report

References

Attachment 1, In- and exclusion criteria

Attachment 2, Variables of dataset