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Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 1115
_____________________________ _____________________________
Improved Nutritional Supportin Cancer Patients
BY
CHRISTINA PERSSON
ACTA UNIVERSITATIS UPSALIENSISUPPSALA 2002
Dissertation for the Degree of Doctor of Philosophy (Faculty of Medicine) in Oncologypresented at Uppsala University in 2002
ABSTRACTPersson, C. 2002. Improved Nutritional Support in Cancer Patients. Acta UniversitatisUpsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of
Medicine 1115. 75 pp. Uppsala. ISBN 91-554-5218-3.
Weight loss and other nutritional problems are common in cancer patients. The problems areof importance for response to treatment and survival and the well-being of the patients.Nutritional support can be carried out in different ways. The efforts considered in this thesis
are; assessment of nutritional status to find the patients who are at risk to become or alreadyare malnourished, assessment of dietary intake, dietary advice, information and support to thefamilies, information and education to the caregivers, and supplementation with drugs thatpossibly could influence the weight development. The Swedish version of the PatientGenerated Subjective Global assessment of nutritional status, PG-SGA, is useful inassessment of nutritional status in cancer patients. Dietary advice and support to patients andtheir families combined with information and education to the staff, at the hospital and in thehome care, turned out to have a positive influence at the weight development and otherparameters related to nutrition. The effects were seen in consecutive patients with small celllung cancer in comparison with a historical control group, and in patients in a randomisedtrial. Fish oil and melatonin could stabilise weight development in patients with advanced
gastrointestinal cancer, but had no marked influence on factors reflecting cachexia. Problemswith nutrition in cancer patients are possible to recognise and various interventions may bebeneficial.
Key words: Cancer, weight loss, PG-SGA, dietary advice, education, fish oil, melatonin.
Christina Persson. Department of Oncology, Radiology and Clinical Immunology,
University Hospital, SE-751 85 Uppsala, Sweden
© Christina Persson 2002
ISSN 0282-7476ISBN 91-554-5218-3
Printed in Sweden by Uppsala University, Tryck & Medier, Uppsala 2002
”Consumed foodis good food ”
Christina Persson
This doctorial thesis consists of the present summary and the following papers, which
are referred to by their Roman numerals.
I. Glimelius B, Birgegård G, Hoffman K, Hägnebo C, Högman G, Kvale G,
Nordin K, Nou E, Persson C and Sjödén P-O. Improved care of patients with
small cell lung cancer. Nutritional and quality of life aspects.
Acta Oncologica 1992; 31(8): 823-832.
II. Persson C, Sjödén P-O, Glimelius B. The Swedish version of the patient-
generated subjective global assessment of nutritional status: gastrointestinal vs
urological cancers. Clinical Nutrition 1999;18(2): 71-77.
III. Persson C, Johansson B, Sjödén P-O, Glimelius B. A randomized study of
nutritional support in patients with colorectal and gastric cancer. In press 2001
Nutrition and Cancer
IV. Persson C, Glimelius B. The relevance of weight loss for survival and quality of
life in patients with advanced gastrointestinal cancer treated with palliative
chemotherapy. Submitted.
V. Persson C, Glimelius B, Rönnelid J, Nygren P. Impact of dietary advice, fish oil
and melatonin on cachexia in patients with advanced gastrointestinal cancer; a
randomised pilot study. In manuscript 2001.
Reprints were made with the permission of the publishers.
All studies were approved by the Research Ethics Committee at the Faculty of
Medicine, University of Uppsala
INTRODUCTION.......................................................................................................7
Cachexia..................................................................................................................8
Energy expenditure and requirements in cancer patients ........................................10
Nutritional status....................................................................................................11
Self-reported weight and height .............................................................................12
Weight loss and quality of life ...............................................................................13
Weight loss and survival ........................................................................................14
Dietary assessment.................................................................................................15
Fish oil and melatonin, possible anti-cachectic drugs .............................................17
AIMS ........................................................................................................................19
MATERIAL AND METHODS .................................................................................20
Assessment methods..............................................................................................21
Assessment of dietary intake...............................................................................21
Quality of life assessments.................................................................................21
Performance status............................................................................................23
Dietary advice........................................................................................................23
Commercial supplements.......................................................................................23
Statistical analyses.................................................................................................24
Study I ...................................................................................................................25
Study II..................................................................................................................27
Study III ................................................................................................................28
Study IV. ...............................................................................................................30
Study V .................................................................................................................31
RESULTS .................................................................................................................32
Study I (Effects of nutritional support in patients with SCLC) ...............................32
Study II (Characteristics of the PG-SGA for nutritional status) ..............................33
Study III (Effects of nutritional support in GI cancer patients) ...............................34
Study IV (Effects of weight loss on survival and quality of life) ............................35
Study V (Effects of fish oil, melatonin and dietary advice on cachexia) .................35
DISCUSSION ...........................................................................................................38
The relation between weight loss and quality of life...............................................38
The relation between weight loss and survival .......................................................40
Assessment of nutritional status .............................................................................40
Assessment of the dietary intake ............................................................................41
Dietary advice, "Consumed food is good food"......................................................42
The role of commercial supplements......................................................................42
The relation between weight development and dietary intake.................................44
The food at home...................................................................................................45
The food at the hospital..........................................................................................45
Information and education to staff at the hospital and in home care .......................46
Weight development and the use of anti-cachectic drugs........................................47
Nutritional support and cancer treatment................................................................48
CONCLUSIONS.......................................................................................................49
ABBREVIATIONS...................................................................................................51
ACKNOWLEDGEMENTS.......................................................................................53
REFERENCES..........................................................................................................54
APPENDIX...............................................................................................................72
7
INTRODUCTION
Nutritional support for cancer patients includes several aspects. The most central are
identification of patients who are at risk to become or who are already malnourished;
dietary advice to patient and family; information and education of all staff involved in
the care of the patient, at the hospital and at home; drugs and other interventions to
relieve symptoms preventing adequate food intake, as well as a variety of intensive
interventions like enteral and parenteral supplies of nutrition. It appears today as if an
increased energy intake is insufficient to stop weight loss among cancer patients and to
achieve weight gain. Several attempts have been made to use possible anti-cachectic
and appetite stimulating drugs (1). Earlier nutritional support was often synonymous
with parenteral or even total parenteral nutrition. Nutritional deficiencies were often
not properly recognised until the terminal stage of the disease, when such development
can not be reversed. As many as 20% of patients with cancer die from the effects of
malnutrition rather than the malignancy itself (1).
In several articles, Tchekmedyian and co-workers discusses the benefits of nutritional
support and the assessment of nutritional status in cancer patients (2-5). He states that
the endpoints for clinical treatments traditionally have been the impact on the
malignancy and survival time. But having a better quality of life (QoL), e.g. feeling
and functioning better and living a worthwhile life are outcome variables of ultimate
interest to the patient. The American Society of Clinical Oncology has stated that as a
single outcome, not even overall survival is sufficient to adequately describe treatment
results (6).
8
Nutritional assessment is a comprehensive process of identifying individuals and
populations at nutritional risk and of planning, implementing and evaluating a course
of action (7). In 1979, Maurice Shils emphasised the need for early and recurrent
assessments of nutritional status in cancer patients (8). Early identification of patients
who are malnourished or who are suspected of developing malnutrition makes it easier
to prevent further nutritional deterioration and to maintain or improve QoL (9,10).
Cachexia
Cachexia and starvation are separate expressions of malnutrition. Starvation is
characterised by pure caloric deficiency, leading to adaptation to conserve lean mass
and to increase fat metabolism. Appropriate feeding may reverse these changes.
Cachexia includes a wide range of metabolic, hormonal and cytokine-related
abnormalities. One characteristic of cachexia is an inability to use nutrients effectively
(11,12) and feeding does not reverse the accompanying metabolic changes (13).
Patients with cachexia lose roughly equal amounts of fat and fat-free mass, but
maintain extracellular water volumes. The acute-phase response (APPR), developed to
localise injured cells and to clear tissue debris, has nutritional implications. High rates
of hepatic protein synthesis are energy- intensive and require large quantities of
essential amino acids, causing loss of skeletal muscle. Changes in fat metabolism are
seen in cachexia, including hypertriglyceridemia, an increased hepatic secretion of
very-low-density lipoproteins and a decrease of lipoprotein lipase activity. Peripheral
insulin resistance alters carbohydrate metabolism. Glucose is redirected to the liver
and other viscera and away from skeletal muscle, and the energy needs of muscle are
met by oxidation of nonessential amino acids, contributing to a negative nitrogen
balance (13) Cancer patients fail to adapt metabolism to save protein stores (14). In
9
critically ill patients, there is an inability of hypercaloric feeding to increase lean body
mass, especially skeletal muscle mass (15,16).
Metabolic abnormalities seen in cancer patients may be caused by cytokines produced
by the host in response to tumour presence (17). Various cytokines participate in a
complex network. The amount and type of dietary fat may influence cytokine
production and activity (11). The tumour necrosis factor α, (TNF-α), is a potent
anorexia-producing agent, promoting skeletal protein wasting, reducing the synthesis
of lipids by inhibiting lipoprotein lipase, and stimulating neoangiogenesis (18,19). The
serum levels of TNF- α are discontinuous and correlated to weight loss (20). High
serum levels of Interleukin-1 β (IL-1 β) cause increased resting energy expenditure
(REE), skeletal protein wasting, reduction of meal size and meal duration (18,19,21),
and are associated with the levels of plasma-fibrinogen and serum C-Reactive Protein
(CRP), and with survival (22,23). Interleukin 6 (IL-6) is associated with weight loss
and increased levels of CRP and Fibrinogen and a decrease of serum-albumin (S-alb)
levels (24, 25). The soluble Interleukin-2 receptor (s IL-2r), necessary for the activity
of the immunoregulatory cytokine Interleukin-2, is elevated in cancer patients, and
significantly higher in cachectic patients. sIL-2r is suggested to be a nutritional
parameter, correlated with P-prealbumin (P-prealb), S-transferrin and survival (26).
Interleukin -8 (IL-8), a proinflammatory cytokine, is involved in the regulation of
satiety and in modulation of the CRP-levels (27, 28).
The majority of the present studies concern attempts to diminish and reverse weight
loss, a clinical sign of cachexia, involving several efforts to increase energy intake and
an intervention with two possible anti-cachectic drugs, melatonin and fish oil.
10
Energy expenditure and requirements in cancer patients
In most nutritional studies of cancer patients, dietary intakes have been compared with
the recommended daily intake (RDA) for healthy subjects (29). Such comparisons
may be relevant but are plagued by the important question: Is energy expenditure, and
thus requirement, higher in cancer patients than in non-cancer individuals?
Total energy expenditure (TEE) involves REE (approximately 70%), voluntary energy
expenditure (25%) and energy expended in digestion (5%) (13). REE is defined as the
metabolic rate in kilocalories (kcal) per day of a postprandial individual, more than
two hours after a meal, lying in bed in a comfortable environment. REE may be
measured by the doubly labelled water method (30), by indirect calorimetry (31) or
calculated by the equations of Harris and Benedict (H&B), (31, 32) or the World
Health Organisation (33).
More than 50% of malnourished cancer patients have an abnormal REE, 33% are
hypometabolic and 26% hypermetabolic (34, 35). In one study, hypermetabolic
patients had a significantly longer disease duration than did normometabolic patients,
33 vs 13 months (35). The primary tumour site was a major determinant of REE.
Oesophageal and colorectal cancer patients were generally normometabolic; patients
with pancreatic and hepatobiliary tumours tended to be hypometabolic and patients
with gastric cancer tended towards hypermetabolism (34).
REE, measured by indirect calorimetry and calculated by H&B, has been compared
between cancer patients, and non-cancer individuals (36) REE was significantly higher
in cancer patients, irrespective of weight loss. Predicted energy expenditure (EE)
agreed with that measured in weight-losing cancer patients. The conclusion was that
11
many cancer patients with solid tumours have an elevated REE, but it is unclear if this
represents a lack of adaptation to undernutrition or a true increase of the metabolic
rate.
In patients with lung cancer, an elevated REE was seen in 70 %, related to the level of
inflammation. A statistically significant difference was seen in the REE between
patients with a weight loss less than 10%, and those with a greater weight loss, 23.4
and 25.3 kcal/kg body weight (BW), respectively (37).
In patients with newly detected gastric and colorectal cancer, preoperative REE was
20.5 kcal/kg BW and increased moderately postoperatively, or to 22 kcal/kg BW (38).
In cachectic patients with pancreatic cancer, REE was significantly higher than in
healthy controls, 24 and 19 kcal /kg BW, respectively (39).
The studies cited above do not give a uniform answer to the question about EEs in
cancer patients. Thus there is no specific recommendation for cancer patients, why the
calculated values in the present studies are compared with the Swedish (SNR) and
Nordic recommendations (NNR) (40) for daily intake in healthy subjects.
Nutritional status
There are several methods for assessing nutritional status. Anthropometric
measurements and laboratory tests are the ones most frequently used. Among the
anthropometric measures, weight and weight development are the easiest to obtain,
and have been found to be useful (17). Weight loss should be evaluated in relation to
usual or pre-illness weight. Loss of subcutaneous fat and muscle wasting are other
12
aspects that may be used to assess nutritional status (41). Serum proteins, especially S-
alb measurements, are often utilised in nutritional studies (42). S-alb measurements
have a predictive value by differentiating low-risk from high-risk patients (41). Low S-
alb is an independent prognostic factor for survival in patients with lung and colorectal
cancer (44-48). However, other data indicate that P-prealb, may be a better marker of
nutritional status than is S-alb (49,50). Also, CRP and P-fibrinogen are associated with
weight loss and survival (51-53).
In addition to these anthropometric and biochemical variables, a standardised
questionnaire may be used to achieve more detailed information, e.g, about diet and
gastrointestinal problems (1). Such a questionnaire, the Patient-Generated Subjective
Global Assessment of nutritional status (PG-SGA) will be presented and discussed.
Self-reported weight and height
Information about BW and height is necessary for calculation of REE, and for the
body mass index (BMI,(kg/m2). It is well-known that there are both under- and
overreporters of weight, but little is known about cancer patients in this respect.
In NHANES II, the National Health and Nutrition Examination (54), the replies from
11284 participants to questions about " what is your weigh without clothes or shoes?"
and "how tall are you without shoes" were compared with measured weight and
height. There was an overall tendency for men to overreport their weight whereas
women underreported it. Underweight men and women overreported their weight,
whereas overweight men and women underreported it. Severely overweight young
men and women (20-34 y) underreported more than did the elderly (55-74y). Both
13
men and women overreported their height, older (45-74 y) more than younger (20-44
y). The association between self-reported and measured weight was calculated in an
American-Danish study (55). Data were collected from applicants for medical
insurance at seven sites in the USA, of which four were obesity treatment sites, and
one site in Denmark. There were strong correlations both in the American (r=0.974)
and Danish data (r=0.856). The conclusion was that it is possible to carry out valid
studies of weight status by questionnaires and even by telephone interviews. Both
methods are used in the present studies.
Allan Detsky (41,56,57) has developed a standardised instrument called the Subjective
Global Assessment (SGA). This method classifies patients into SGA A (well-
nourished), SGA B (moderately /suspected malnourished) and SGA C (severely
malnourished). The SGA has been used for assessment of nutritional status of patients
with various diseases (58,59). It has been translated into Swedish and tested for
validity and reliability in studies of patients undergoing gastrointestinal surgery and in
patients at geriatric clinics (60, 61). A modified version of the SGA has been
developed, the PG-SGA, intended for use with cancer patients (62, 63). This version
differs from the original SGA, in that the patient completes the first four questions and
the clinician, dietician or nurse the remaining ones.
Weight loss and quality of life
Malnutrition and weight loss may influence QoL. Previous studies have shown lower
QoL scores and more appetite loss and fatigue in patients with weight loss than in
those without weight loss (64-67). A significant correlation has been reported between
performance status and weight loss in patients with colorectal cancer (66,68). APPR,
14
with a lowered level of S-alb and an increased level of CRP were seen at baseline in
weight losing gastrointestinal (GI) cancer patients. At follow up, CRP continued to
increase and performance status decreased in weight losing patients (51). In a study of
199 patients (65) with locally advanced and/or metastatic GI cancer, weight loss and
reduction of appetite were related to a reduced QoL. Patients with weight loss, median
17%, had a lower Karnofsky performance score (KPS) (69) than did weight stable
patients. Patients with weight loss had significantly more problems with fatigue,
nausea and vomiting and appetite. To examine whether weight loss at presentation had
an influence on outcome, data were collected from patients with locally advanced or
metastatic GI cancer (66). All patients were treated with chemotherapy. Patients
continuing to lose weight during the first 120 days of treatment had a lower mean
QoL, all sites combined, than did patients with stabilised or increased weight.
The above mentioned relations between weight loss, QoL and performance status
reported in previous studies will be further explored in the present studies.
Weight loss and survival
Involuntary weight loss, often seen in cancer patients, carries prognostic information
in studies of a variety of tumours (45-48,66,68,70-74). In patients with colorectal and
gastric cancer, a statistically significant difference in survival has been demonstrated
between those with and without weight loss (68). In patients with SCLC, weight loss
and a reduced S-alb, are significant determinants of survival (48,74). APPR, and low
performance status have been found to be associated with poor survival in GI cancer
patients, independent of weight loss (52).
15
Overall survival was significantly improved in GI cancer patients when a stabilisation
of weight loss occurred (66). Average time of treatment was shorter in patients with
weight loss. In a multivariate analysis, four independent prognostic variables of overall
survival were found: weight loss, performance status, response, and presence of liver
metastases.
Preoperative weight loss has predictive value for postoperative mortality and survival
in studies including patients with gastric and colorectal cancer (47,68). In surgically
treated patients with gastric adenocarcinoma, weight loss (73), low S-alb levels and a
high nutritional risk index NRI (47) were significantly correlated to survival.
The predictive value of involuntary weight loss and a deficient nutritional status will
be explored in the present studies.
Dietary assessment
The objectives of a dietary study are to assess past and/or present dietary intake, long-
term effects of diet on nutritional parameters, or the impact of interventions on dietary
intake in specific high-risk groups. There are a variety of methods for assessment of
dietary intake. The most commonly used are food frequency questionnaires, food
records (estimated or weighed) and 24-hour recalls. The 24-hour recall is considered to
be reliable for assessing intake of groups (75-78). A comparison has been performed
between weighed records, 24-h recalls (unstructured and structured), food-frequency
questionnaires and estimated-food diary (79). Data from the food diary, combined with
a booklet with photographs of three portion sizes were most closely associated with
16
the weighed record. However, the unstructured 24-hour recall compared surprisingly
well with the weighed records.
Examples of errors that might occur in dietary assessment studies are; foods or eating
events are omitted, over- or underestimated amounts, food types are not sufficiently
described, amounts of foods are not correctly quantified, an incorrect food code is
selected in the nutrient database, and volume to weight conversion factors may be
wrong.
The 24-hour interviews may be performed by telephone or face-to-face. Good
agreement between the two methods has been reported (80,81). In comparison with
observed meals, the accuracy of telephone recalls with respect to portion-size and
number of food items appears to be adequate (82,83). As the 24 hour-recall interview
implies that the person has to remember everything consumed during the past 24
hours, fading memory can be a problem, and patience and care must be shown by the
interviewer. A check-list is helpful to remind the interviewer to ask about snacks,
drinks between meals, candy, fruit etc, not always considered to be food. The food
items are described in household measurements in terms of glass, cup, spoon and,
when possible, in grams or dl. The cooking process should also be described (cooked,
fried, grilled or raw).
Other sources of error in dietary assessments are underreporting or bias due to social
desirability. Biased reporting in 24 -hour recalls may result from selective forgetting of
socially undesirable foods, or purposeful fabrication of socially desirable responses
(84). The frequency of underreporting has been studied in the NHANES III study,
where 24-hour recalls were used (85). Fewer men than women were underreporters, 18
17
and 28%, respectively. The prevalence of overweight and attempts to lose weight was
significantly higher in underreporters, both men and women. The ratio between
estimated energy intake and estimated basal metabolic rate was used to evaluate
underreporting of dietary intake. Biased over- or underreporting is a characteristic of
some persons.
In the present studies, assessment of dietary intake was performed using the 24-h
recalls. A 4-day food diary was used in another.
Fish oil and melatonin, possible anti-cachectic drugs
Fish oil, containing omega-3 fatty acids has been suggested as a drug for the treatment
of cancer cachexia (86). The omega-3 fatty acids eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) inhibit cytokine production and activity by interfering
with the cyclo-oxygenase and lipid-oxygenase pathways (18). Omega-6 fatty acids,
linoleic acid and arachidonic acid (AA) may increase the production of prostaglandin
E2 (PGE2), whereas omega-3 fatty acids reduce this production. An antitumour effect
of fish oil seems to be the result of a reduction of tumour cell proliferation through
reduced levels of PGE2 and its metabolites (87). Omega-3 fatty acids modulate the
metabolic response to feeding (22), and reduce the levels of CRP, TNF-α and IL-6 (88,
89). In previous studies supplementation with fish oil has shown associations with
weight gain, improvement in performance status, better appetite, and survival (90, 87).
Fish oil in combination with nutritional supplements prevented progression of APPR
and cachexia in patients with advanced cancer (91).
18
Melatonin is a hormone produced by the pineal gland, and patients with advanced
cancer often present with a pineal endocrine hypofunction. This secretion shows a
circadian rhythm with the lowest values during the day (92,93). Melatonin reduces the
levels of circulating TNF-α, and the degree of weight loss (92,93). An improvement in
performance status was seen in patients with metastatic GI cancer treated with
melatonin (92).
Corticosteroids have been used for appetite stimulation in cancer patients. Excellent
short-term effects have been seen (94). However, chronic use requires increasing doses
to maintain the effect, which results in side effects like muscle wasting and weakness,
immunosuppression, diabetes, and osteoporosis (94). Progestins, e.g. megesterol
acetate (MA) and medoxyprogesterone acetate (MPA) have been used extensively as
appetite-stimulating drugs in cachectic cancer patients. MPA vs placebo during 12
weeks led to a statistically significant increase of energy intake and fat mass (95). MA
and ibuprofen compared to MA and placebo resulted in a statistically significant
increase in appetite scores in both groups. However, median weight decreased in the
MA-placebo group, while a significant increase was seen in the MA-ibuprofen group.
The authors suggest that the anti-inflammatory effect of ibuprofen contributed to the
weight gain (96). In a review of 15 randomised clinical trials, significant
improvements were seen in appetite and in body weight gain in patients treated with
high dose progestins (97).
19
AIMS
The aims of the present thesis are twofold: to study weight loss, and to explore the
possibility to influence the development of body weight in cancer patients.
The following research questions were formulated:
Is weight loss related to quality of life, response to treatment and survival in
patients with colorectal, gastric, biliary and pancreatic cancer? (Study IV)
Does an instrument for assessment of nutritional status, the PG-SGA, facilitate an
early identification of cancer patients at risk to be or already malnourished? (Study II)
Is it possible to regain weight or prevent further weight loss among cancer patients by
providing dietary advice, support and information to their families, information to and
education in nutritional issues of hospital and home care staff? (Study I and Study III)
Does supplementation with two possible anti-cachectic drugs, melatonin and fish oil,
influence the weight development and markers of cachexia among patients with
advanced gastrointestinal cancer? (Study V)
20
MATERIAL AND METHODS
Diagnoses and numbers of patients in studies I-V are shown in Table 1.
Table 1. Diagnoses and the number of patients in the included studies
Study I
Small cell lung cancer 58 vs 81 historical controls
in nutritional, response and
survival parameters.
36 vs 22 in QoL parameters
Study II
Gastrointestinal and 54 vs 33, consecutive patients
urological cancer at the out-patient clinic
Study III
Gastric and colorectal cancer 71 randomised to nutritional
support vs 73 controls
Study IV
Gastric, pancreatic, 152 patients treated within four
biliary and colorectal cancer randomised studies
Study V
Gastric, pancreatic, 24 patients with weight loss
biliary and colorectal cancer and/ or S-alb below 35
21
Assessment methods
Assessment of dietary intake
The 24-hour recall method was used in Study I, and the initial interview was made on
the ward the first time the dietician met the patient. The subsequent interviews were
made by phone. The same method was used in Study III, the first interview as far as
possible conducted in the patient's home and the subsequent interviews by phone. The
dietician used a booklet with black-with drawings and photographs of different portion
sizes at the first interview. In Study V, a 4-day food diary was employed combined
with a booklet with colour photographs, which the patient kept at home during the
study. The patients received written information on how to complete the food diary.
In Study I the calculations of dietary intake were made with a computer program from
Kost-och Näringsdata (98), and in Studies III and V with the MATS program (99).
Quality of life assessments
Three different questionnaires were used for assessment of quality of life in the
included studies (Table 2).
Table 2 Quality of Life assessments
Study I Cancer Inventory of Problem Situations, CIPS
Studies III, IV and V EORTC-QLQ C-30
Study IV Uppsala Questionnaire (in part)
22
The Swedish version of the Cancer Inventory of Problem Situations (CIPS) (101) was
used in Study I. The CIPS is a cancer-specific survey instrument designed to assess
day-to-day problems and rehabilitation needs. During an interview, patients rated how
much they agreed to 131 problem-oriented statements using a scale from 0 to 4, a
higher value indicating more problems. CIPS-items were combined into higher-order
factors and subscales, representing physical, psychosocial, medical interaction, marital
and sexual problem areas, proposed for the original CIPS (102,103).
The EORTC QLQ C-30 is a 30-item questionnaire, often used for assessment of
health-related QoL among cancer patients (104). The EORTC QLQ-C-30 is a
multidimensional instrument that covers physical, social and psychological
functioning as well as cancer-specific symptoms. The 28 items measuring physical,
role, emotional, cognitive and social functioning, symptoms and financial difficulties
have a four-grade scale. The two remaining items concerning global quality of life has
a seven-grade scale. Subscale scores are transformed to 100 grade scales. In the
functional scales and in the score for global health/QoL, a higher value means a better
QoL. However, a higher value on a 0-100 symptom scale indicates more problems.
The Uppsala Questionnaire is a structured questionnaire centred on problems of daily
life (105). It consists of five parts. 1. Pain, location indicated on a schematic drawing,
and intensity rated on a 1-10 scale. 2. Symptoms and adverse effects, the occurrence of
25 events e.g. loss of appetite, tiredness, changed tates sensations. 3. Frequency of
troublesome events i.e. resting, crying, skipped meals, problems concentrating, and
consumption of analgesics was rated on a 4-step scale. 4. Nausea, vomiting, diarrhoea,
intensity and frequency, and 5. tiredness and pain in association with everyday
activities, rated on a 0-10 scale.
23
Performance status
The Karnofsky Performance Status (KPS) is used for assessment of performance
status, yielding a numerical value, in terms of percentage, describing the patient's
ability to carry on his/her normal activity and work, his need for a certain amount of
care, or dependence on constant medical care (69).
Dietary advice
As many of the patients did not manage to eat large portions, they were often advised
to have an energy-dense diet to satisfy their energy requirements. The easiest way to
increase the energy content of food is to add fat. In the recommendations for diets in
Swedish hospitals (100), the recommended level of fat in an energy-dense diet is 35
energy per cent (E%). This should be compared with the Nordic recommendation for
healthy people, which is<30% (40). To increase energy intake, the patients were also
counselled to have more sweet drinks and desserts, in contrast to the dietary advice to
healthy people. The patients were told to have small but frequent meals, and to use
commercial supplements and enrichments, both liquid and in powder form.
Commercial supplements
The majority of the supplements used were complete liquid supplements containing
protein, fat, carbohydrates, vitamins and minerals. There were some without fat, but
they were seldom recommended. Enrichments were available as powder or liquids,
complete as the liquid products or containing only carbohydrates or protein. The
supplements were available in many different flavours.
24
Statistical analyses
Comparisons of mean values were in Studies I-V performed by the unpaired Student's
test in body weight, BMI, KPS, biochemical and QoL variables. The paired t-test was
used in Study V, comparing QoL assessments at two different points of time.
The Mann-Whitney U test was used for comparison of median values in biochemical
variables and levels of cytokines (Study V).
Analysis of variance was used for between-groups changes over assessments in body
weight (Study I) and BMI (Study III). In Study II, analysis of variance was performed
for comparison of biochemical variables in the three SGA-classes
In Study V, the Wilcoxon signed rank test was used for changes within groups over
assessments in the biochemical variables and the levels of cytokines.
The Chi-square test was performed to test proportions in weight loss and decreased S-
albumin between groups (Study I), and diagnoses in the different SGA-classes (Study
II).
Correlations were analysed by the Pearson coefficient between weight loss and
biochemical measurements (Study II), weight development and global QoL, and
weight development and fatigue (study III), and between symptoms, KPS and global
QoL (Study IV).
The Spearman rank coefficient was performed for correlations between the
biochemical variables and the levels of cytokines in Study V.
25
The relationship between the different components of the PG-SGA was analysed by
logistic regression (Study II).
Hazards ratios of the significant prognostic variables of survival were calculated using
the Cox regression model (Study IV).
Multivariate regression was performed in analysing variables explaining global QoL
(Study IV).
The inter-rater reliability was analysed by Kappa statistics (Study II)
Cumulative percent surviving was in all studies calculated with the life-table technique
and differences were tested with the log-rank test.
Study I
This study is based on a cancer care project financed by the Swedish Cancer Society,
which started in February 1987 and was terminated in December 1989. The purpose
was to improve patient care, both in general terms as well as in certain specific
respects. The patients suffered from one of the following diagnoses: Small cell lung
cancer (SCLC), high grade non-Hodgkin lymphoma, Hodgkin's disease, acute
leukaemia, myeloma in progressive stage, and breast cancer Stage II to be treated with
adjuvant chemotherapy. Only patients with SCLC are included in the present paper.
All patients were treated with intensive combination chemotherapy. A description of
the project and its overall results has been published elsewhere (102). A special nurse
was employed on each ward participating, a contact nurse, who played an important
26
role in the project. There was also a common "resource group" consisting of a nurse,
psychologists, social worker, dietician, occupational therapist and physiotherapist. A
care program booklet was produced giving guidelines and detailed descriptions of
goals and methods. Some of the main points were information, communication, crisis
reactions, activation, and care-taking of families and relatives, nutrition, pain and
nausea treatment. For the SCLC patients, the intervention efforts were concentrated on
their nutritional situation. Weight and nutritional parameters were recorded repeatedly,
in connection with every course.
The study period group (SPG) consisted of fifty-eight patients with SCLC, and in the
evaluation of the nutritional and survival outcomes, another 81 patients served as
historical controls (S/N-C). They had received the same medical treatment before the
project started. The latter group had not had the possibility to meet a contact nurse, to
get nutritional support from a dietician or access to the resource group. Data on
weight, S-alb, B-Hb, stage and KPS in the control group were collected retrospectively
from the clinical records.
The main instrument of evaluation was the CIPS (101). Interviews with patients in the
SPG were made before the second treatment course, and in association with the 4th,
8th and 12th course. One month before the care project was initiated, twenty-two
patients, treated for a mean of 7.1 courses, were interviewed with the same instrument.
In the QoL evaluation, these patients served as a control group (QoL-C) to the thirty-
sex patients assessed in association with their 8th course.
The SPG patients all met the dietician in connection with one of the first treatment
courses and then repeatedly on the ward during treatment. Dietary assessments, 24-
27
hours recalls by phone, were done at regular intervals, before every 4th treatment
course, followed by individual dietary advice. Families and relatives were also
involved. They met the dietician on the ward, talked to her on the telephone when the
patient was at home and attended meetings arranged during the project.
An extensive educational program was offered to all employees at the wards.
The staff was taught the importance of nutritional support and good nutritional status.
To facilitate the nutritional care on the ward, a special diet-cardex was compiled with
information about diet, such as what supplements the patient preferred, and foods that
the patient did not like. The diet-cardex was kept in the kitchen on the ward. During
the study, a new way to serve the food was introduced. Food was delivered in deep
dishes instead of ready-made trays. Meals were served at laid tables in the day room
instead of at the bedside.
Study II
The aim of the study was to translate the PG-SGA into Swedish and then evaluate the
instrument in an outpatient setting. Two groups of patients were compared, one in
which nutritional problems and a poor nutritional status are frequent, i.e. GI cancer,
and the other where these are infrequent, i.e. urological cancer. During the period
February to December 1996, the nutritional status of 87 consecutive patients was
assessed at the outpatient unit of the Department of Oncology, Akademiska hospital,
Uppsala. All patients with gastric, pancreatic, biliary and anal cancer had inextirpable
primary and/or metastatic disease. None of the patients with testicular cancer had
known metastases.
28
The PG-SGA was translated into Swedish and then back-translated by a nurse from the
USA. Then it was retranslated into Swedish after comparison of the two versions. The
questionnaire is reprinted in Appendix. When arriving to the out-patient unit, the
patients received written information about the study, and if they agreed to participate,
they completed their part of the SGA (questions 1-4). These questions concerned
actual weight, weight six and twelve months ago, gastrointestinal problems, food
intake, and physical activity.
The physician completed the remaining questions concerning diagnosis, metabolic
demand, loss of subcutaneous fat, muscle wasting and oedema. The classification of
each patient’s nutritional status as A, B or C was based on the answers from the patient
and the physician. Without knowledge of the doctor's assessment and classification,
the dietician completed the same questions as the doctor and made an independent
classification. In order to validate the classification, biochemical measurements S-alb,
P-prealb, B-neutrophils and B-lymphocytes, were performed.
After answering the PG-SGA, the patients were offered to meet the dietician for
dietary advice. When required, prescriptions for commercial supplements were also
given.
Study III
Within a "Support-Care-Rehabilitation" project, patients with breast, prostate,
colorectal or gastric cancer were randomised to one of four alternatives: 1. Individual
Support (IS), starting at diagnosis, including intensified primary health care (IPHC),
problem-focused psychological support (IPS) and individual nutritional support (NS).
29
2. Group Rehabilitation (GR) 3. A combination of Individual Support and Group
Rehabilitation (IS+GR) and 4. Standard care (SC). Patients were included between
October 1st ,1993 and December 31st ,1995. The intensified primary health care (IPHC)
included in IS implied that the patient was referred to the home care nurse responsible
for the district where the patient lived. The patient's general practitioners (GP) were
informed about the cancer diagnosis and the referral to the home care nurse. The IPHC
has been evaluated and described elsewhere (107-109). The individual psychological
support (IPS) was designed to identify the patient's needs on an individual basis, and
to help them to handle problems arising from the diagnosis and medical treatments.
The patient was contacted by phone and a first appointment was decided. The
psychologist then suggested appropriate psychological interventions based the patient's
needs. The IPS has been described and evaluated elsewhere (110,111). The GR
intervention was an eight-session group intervention with a booster session, starting
approximately 4 months after diagnosis. Each group consisted of 3-9 patients. An
oncology nurse, a psychologist and a physiotherapist conducted the sessions. The
sessions included cognitive behavioural therapy techniques and light physical training
plus relaxation. In one session, an oncologist or a surgeon gave information about
disease and treatment, and the dietician participated in one session. The GR
intervention has been described elsewhere (112,113). The nutritional support (NS)
described in the present paper was offered to patients with colorectal or gastric cancer,
randomised to IS. The aim of Study III was to evaluate if NS affects weight
development, food intake, QoL and survival in patients with GI cancer.
Sixty-seven patients with GI cancer were randomised to IS+ISGR, the study group,
and 70 to GR+SC, the control group. All patients in the IS+ISGR group accepted the
NS they were offered. Weight development and QoL aspects were evaluated in both
30
groups, at diagnosis and after 3, 6, 12 and 24 months. In the study group, dietary
intake was assessed by 24-hour recalls on the same occasions. In patients with
advanced disease, there were additional assessments of the dietary intake. The first
contact was made as soon as possible after diagnosis and randomisation. The living
area, Uppsala town or rural district determined whether the contact was made face-to
face or by telephone. The subsequent interviews were all made by telephone, and in
connection with the interview, family members had an opportunity to talk to the
dietician.
The home care nurses and the general practitioners received education in nutritional
issues prior to and throughout the project. A video was made concerning nutritional
problems and dietary advice to patients with gastric cancer, which was used in this
education. A chapter on nutrition was included in the booklet "Oncology care",
prepared prior to the project and distributed to participating staff. The dietician gave
lectures on nutritional problems in cancer patients, and dietary advice including enteral
nutrition. in seminars arranged by the project group. The dietician also participated in
problem-focused supervision offered to the home care nurses.
Study IV.
To explore the relations between weight loss, other nutrition-associated parameters,
performance status and response to chemotherapy on one hand, and survival and
global QoL on the other, data from patients treated within four randomised studies
were analysed. All the 152 patients had advanced GI cancer, gastric, colorectal,
pancreatic or biliary cancer. Data were gathered from the case record form used in
these studies and from the medical records. The analyses of weight loss, nutritional
31
problems, performance status, and QoL were all based on data at inclusion. in each
study. QoL and presence of symptoms were assessed by the Uppsala questionnaire
(105) in the first study and by the EORTC QLQ C-30 (104) in the remaining studies.
The KPS (68) was used to assess the performance status. Responses to treatment were
classified using the UICC criteria (111). Analyses of survival in relation to whether a
response occurred or not were made according to the landmark method (112,113),
excluding patients who died before the response evaluation or within 120 days.
Study V
Twenty-six patients with advanced GI cancer and a weight loss of ≥ 10% during the
last six months, or S-alb ≤ 35g/L were included. Two patients did not participate in the
intervention, one due to early death and one due to thrombosis. Baseline assessments
were made during the first weeks after inclusion. They included biochemical, QoL and
dietary assessments. Patients were then randomised to a 4-week intervention period
with fish oil (FO) or melatonin (MLT) followed by study assessments and a 4-week
intervention period with FO and MLT, and final assessments. The prescribed amounts
of the supplements were 2x15 ml /day FO or 18 g/day MLT.
Dietary intake was measured by 4-day food diaries at baseline, and after the first and
the second intervention periods. Patients had dietary advice, based on the diaries, at
inclusion, and during the intervention periods. At baseline, and after the first and
second period, B-haemoglobin, (B-Hb), S-alb, S-lactate dehydrogenase (S-LDH), CRP
and P-fibrinogen as well as the cytokines TNF-α, IL-1β, sIL-2 R, IL-6 and IL-8 were
assessed. Levels of fatty acids linoleic acid, AA, EPA and DHA were assessed on the
same occasions, and QoL by means of the EORTC QLQ C-30 questionnaire (104) and
32
the KPS (69). Compliance with the FO regimen was assessed in relation to the
development of plasma levels of EPA. Patients with at least a doubled level of EPA
were estimated to have good compliance. Compliance with the MLT regimen was
assessed in relation to the number of pills consumed. Two empty packages, the
prescribed amount, were considered as good compliance.
RESULTS
Study I (Effects of nutritional support in patients with SCLC)
At diagnosis mean body weight and BMI did not differ between the study group (SPG)
and the control group (S/N-C). However, during the study period, there was a more
pronounced decrease in body weight and BMI in the S/N-C group, than in the study
group (p<0.01 and p<0.05, respectively). Mean S-alb did not differ at diagnosis,
remaining approximately constant in the control group but increased with time in the
study group (p<0.001). Mean energy intake at home was 1530 kcal at the first
interview which increased to 1700 -1800 kcal at the following assessments. Fat
provided 38-42% of the energy.
The routines for nutritional support on the ward were improved, due to the
implementation of the diet-cardex routine and the education. Commercial supplements
were always available as well as popular food like pancakes, meatballs, ice cream, and
milk shakes.
33
Compared with the QoL-C group, the available patients in the study group expressed
fewer problems with weight loss, and appetite in hospital. In patients in the study
group the scores for "food tastes bad" in hospital were significantly lower, p<0.01.
The mean global score of all 131 CIPS-items was lower in the study group than in the
control condition (p<0.001), indicating a better QoL. The changes in CIPS
factors/individual items formed a coherent pattern in that scores were better in the
study group in aspects dealt with, whereas no differences were found in other respects.
There was no statistically significant difference in survival between the two groups.
Study II (Characteristics of the PG-SGA for nutritional status)
The inter-observer agreement for the PG-SGA between doctor and dietician was 90%.
After a joint re-examination consensus was reached about the classification of the
remaining patients. Significantly more patients with urological cancer (91%) than with
gastrointestinal tumours (48%) were classified as well nourished, p<0.001.
Patients classified as SGA B and C had lower S-alb and P-prealb levels than did those
classified as SGA A, but only the differences between SGA A and SGA B were
statistically significant (p<0.05 and p<0.01, respectively). Patients assessed as having
an enhanced metabolic demand had significantly lower means of both S-alb and P-
prealb (p<0.001). Mean weight loss over the last six months was 4.5% (SD 2.6) in
patients rated as SGA A, 7.5% (SD 5.3) in SGA B and 11.2% (SD 5.1) in SGA C.
There were positive correlations between the percentage of weight loss, calculated as
the difference between actual weight and the weight 6 and 12 months ago,
respectively, and the biochemical measurements.
34
A multivariate logistic analysis revealed independent contributions to the SGA
classification by weight loss the last 6 months, altered food intake, problems
preventing the patient to eat enough, physical activity and muscle wastage. The SGA
A group evidenced a significantly longer survival than did the SGA B+C group,
p<0.001.
Study III (Effects of nutritional support in GI cancer patients)
The number of patients decreased with time, mainly due to death caused by the
underlying malignancy. At the assessments at 6, 12 and 24 months, the number of
patients available were 49 v s 52, 41 vs 44 and 37 vs 30 patients, in the IS+ISGR
group and the GR+SC group, respectively.
Despite a tendency for greater weight loss at inclusion (7.2 vs 5.5%), the IS+ISGR
group managed to gain weight more rapidly and to a greater extent than the control
group. The mean group scores differed significantly at 12 and 24 months (p<0.05).
The mean energy intake was rather stable during the study period (1400-1500
kcal/day). However, patients with weight loss at inclusion increased their energy
intake and weight more than those without weight loss. Energy provided by fat varied
between 35 and 40%. There were no differences between the study group and the
control group in the QoL ratings. At inclusion fatigue and loss of appetite had high
scores, meaning more problems, but the scores decreased during the study period. A
positive correlation was seen between weight development and QoL and a negative
correlation between fatigue and weight development. The study group had a
numerically longer survival than the control group, but this difference did not reach
statistical significance (p=0.3).
35
Study IV (Effects of weight loss on survival and quality of life)
Seventy-four per cent of the patients had lost weight at inclusion, mean 7.3%. The
proportion of patients with weight loss and the degree of weight loss were higher in
patients with gastric and pancreatic or biliary cancer than in those with colorectal
cancer. Patients with weight loss had a lower KPS score than did those without weight
loss (p<0.001). Diagnosis had the strongest association to survival, but poor
performance status and weight loss were also independently related to survival. Time
of survival was longer in patients without weight loss (p<0.001). Global QoL scores
were lower in patients having weight loss than in those without weight loss (p=0.01).
Patients who stated problems with pain and fatigue also had lower mean global QoL
values. Weight loss, low performance status, high frequency of nutrition-associated
problems and low B-Hb levels were associated with a lower probability to respond to
treatment.
Study V (Effects of fish oil, melatonin and dietary advice on cachexia)
Among the 24 patients who started with the supplements, FO and MLT, twenty
patients accomplished the first and sixteen the second study period. There was one
drop-out and one patient died in each randomisation group during the first intervention
period. During the second period, there was one drop-out in the FO group and three in
the MLT group, all due to progressive disease.
The cytokines TNF-α, s-IL2R and IL-6 were detected in 100%, IL-1β in 42% and IL-8
in 50% of the patients at baseline. The median values for most of the biochemical
variables were out of normal range in both groups. The MLT group had generally
36
higher baseline cytokine values compared with the FO group. However, this was
statistically significant only for sIL-2R ( p=0.02). During the study period,
biochemical variables and cytokines changed, but not in a systematic way. When
analysing all patients together, the only statistically significant changes were an
increase in IL-6 over the first intervention period and (p=0.04) and in IL-8 over both
intervention periods (p=0.02).
At baseline mean plasma levels of fatty acids were similar to those in healthy
volunteers. After the first intervention period, EPA and DHA increased in the FO
group (p<0.001), whereas there were no changes in the MLT group. The changes in
the FO group were similar to those seen in healthy volunteers taking 30 ml FO/day
during 4 weeks (117). During the first intervention period, good compliance with the
fish oil regimen was seen in 62% and to melatonin in 45% of the patients. In the
patients who started with the supplements the second period, corresponding figures
were 62 and 36%,
At inclusion there was considerable weight loss in both groups, mean 12%. However,
weight stabilised in both groups during the study. During the first intervention period,
4/13 of the patients in the FO-group had a weight stabilisation or gain, compared to
2/11 in the MLT group. The median weight loss was 0.6 kg and 1.8 kg, respectively.
During the second period, weight stabilisation or gain was seen 5/11 of the patients in
the FO group, and in 4/9 in the MLT group. The median weight gain was 0.2 and 0.8
kg, respectively.
The mean energy intake at the three assessments varied between 1500 and 1850 kcal.
37
At baseline the MLT had a lower mean energy intake, 1500 kcal, than the FO group
did, 1750 kcal. During the study period the energy intake increased in the MLT group,
in patients who accomplished the whole study period mean intake increased by 166
kcal. However, in the FO group a reduced energy intake was seen, mean energy intake
decreased by 240 kcal during the study period. Fat provided 33-35 E%, the fish-oil not
included.
The baseline score for global QoL was low, and problems with fatigue and loss of
appetite were common. The global QoL scores increased slightly and problems with
appetite decreased markedly during the study period There were no statistically
significant differences in KPS or QoL between the two randomisation groups, either at
baseline or during the study period.
Neither FO nor MLT or their combination induced major biochemical changes
suggesting strong anti-cachectic effects in these patients with advanced GI cancer.
However, both FO and MLT, combined with dietary advice showed a weight
stabilising effect.
38
DISCUSSION
Several aspects of nutritional support, all of them important in the care of cancer
patients, were dealt with in the present dissertation. The impact of weight loss on QoL,
survival and response to treatment was explored; a questionnaire for the assessment of
nutritional status was translated and evaluated; and the effects on weight development
of dietary advice and support of patients and families by a dietician were studied. An
extensive educational program was carried out, including doctors, nurses and assistant
nurses at the hospital and in home care. In a pilot study, possible effects on cachexia
by two anti-cachectic drugs in addition to dietary advice were explored.
An early identification of patients at risk for malnutrition should make it possible to
prevent further nutritional deterioration. Weight and weight development are the
primary candidates for parameters that can be used to identify patients at risk for
malnutrition or already malnourished. In the present studies, weight loss at inclusion
varied between a few percent in patients with testis cancer to above 10 percent in
patients with advanced upper abdominal cancer. Weight loss was seen predominantly
in patients with advanced disease.
The relation between weight loss and quality of life
For many people a high QoL includes the ability to enjoy food and drink. Loss of
appetite, nausea, vomiting and fatigue may prevent cancer patients from participating
in and enjoying meals with families and friends. In earlier studies weight loss has been
associated with a low QoL (64-66,118). Such associations were also seen in Studies I,
III, IV and V. QoL improved when patients gained weight (Study III), and when there
39
was a less pronounced weight loss (Study I) or a stabilisation of the weight
development (Study V).
Fatigue leads to a reduced level of motivation or interest in engaging in activities and
to difficulties to complete tasks of daily living (119). This may include less interest in
food purchase, cooking and eating. In the Swedish reference population for the
EORTC QLQ C-30 (120), age group 60-69 years, the mean value of fatigue was
approximately 20. At inclusion in Study III, the mean value was 46, and in Study V
corresponding figures were 54 in the FO group and 72 in the MLT group.
Loss of appetite, is a symptom that may lead to weight loss. At inclusion in Study V,
appetite loss was a major problem among the patients. The mean score was 60,
compared to 4 (women) and 2.4 (men) in the reference population (120). A decrease in
the appetite scores was seen during the study period, but the subsequent mean scores,
about 40, show that the patients continued to have substantial problems. However, the
MLT group who had the lowest intake at baseline managed to increase their energy
intake, and a weight stabilisation was seen in both groups. In Study I an improvement
of the items "food tastes bad at hospital", and "weight loss" was reported by the study
group. This may be related to the change of system of serving the meals, suggesting
that the way the food is served may affect appetite.
Still, the most efficient way to improve cancer patient's nutritional problems and poor
QoL is to actively control the tumour, but this is not yet possible for many of the
cancer diseases. However, efforts to limit weight loss that are implemented as soon as
possible may contribute to a better QoL. The loss of appetite, shown to be associated
40
with lower QoL scores in weight losing cancer patients (64-67) may be stimulated by
drugs e.g. progestins (94-96).
The relation between weight loss and survival
The prognostic role of information on weight loss reported in other studies (45-
48,66,68,70-74) was also seen in Studies II, III and IV. In Study II weight loss the last
6 months showed an independent contribution to the overall classification of
nutritional status. There was a statistically significant difference in time of survival
between the patients rated as SGA A and those rated as SGA B+C. In Study III, there
was a numerical, but not statistically significant difference in time of survival between
the study group, which experienced a more rapid and greater weight gain, and the
control group. Weight loss was also independently related to survival in Study IV,
with a statistically significantly longer time of survival in patients without weight loss.
Weight losing patients had a lower probability to response to chemotherapy treatment
(Study IV). Hence, efforts to prevent further weight loss may have an impact on
survival in cancer patients.
Assessment of nutritional status
Malnutrition may be present even in the absence of marked weight loss (52).
Biochemical variables, e.g. S-alb, B-Hb, CRP and Fibrinogen, often assessed as a
routine, may reveal a deteriorated nutritional status (42,44-48,52,53,121). Low S-alb
levels have earlier been demonstrated to correlate with a deficient nutritional status as
previously assessed by the SGA (58). In study II a similar relationship was
demonstrated, now using the PG-SGA.
41
If reliable biochemical variables are not available, a questionnaire may be employed to
assess nutritional status. The PG-SGA (Study II) was shown to be a simple, reliable
and cheap method for assessing nutritional status in the two groups of patients that
were selected to differ considerably in their nutritional status. However, in patients
with advanced cancer the question about the level of food intake last month compared
to normal may be less reliable. In these patients the actual food intake may be very
small, but considered as normal by that patient for quite some time. It is possible that
the PG-SGA is more suitable for newly diagnosed cancer patients, the majority of
whom are unlikely to have an advanced disease.
Assessment of the dietary intake
Dietary advice should always be based on the patient's actual food intake, assessed in a
proper way. The 24-hour recall for assessment of food intake is considered to be the
easiest method for the patient, but calls for the interviewer to be very careful. The
decision to use this method in Studies I and III was made in view of its simplicity for
the patients, still being discriminative and providing relevant information. However,
when the food diary method was used in Study V, we realised that even patients with
very advanced disease managed to complete this without considering it too
burdensome. In future studies, we recommend use of the food diary, based on our
experience and the demonstrated stronger correlations with weighed records (79).
One may speculate about under- and overreporters among cancer patients. As many of
them have lost weight/are losing weight and have difficulties eating enough, there does
not seem to be any reason for them to underreport. Perhaps there are more
overreporters to satisfy the interviewer, especially if this is the dietician responsible for
42
the dietary advice? However, the rather modest dietary intake reported in the 24-hour
recalls and in the food diaries do not support this notion.
Dietary advice, "Consumed food is good food"
Dietary advice to the patients was based on the notion that the food the patient
managed to eat was good for him/her, regardless of nutritional composition. They
were told that cream, butter, whole fat milk and cheese, desserts and sweets were
"good food", and that the main purpose was to get as many calories as possible. This
message was sometimes met with surprise and even suspicion from patients and their
families, even if given both by the treating doctors, the nurses and the dietician. This
advice is the opposite to that given for prevention of cancer or other diseases, which
necessitated considerable explanations. The only disadvantage of this message was
that family members sometimes were worried about gaining weight, when they had the
same food as the patient.
In Study V, however, the dietary advice was different. The patients were told to reduce
their intake of food with a high amount of fat, in order to reduce the competition
between "the ordinary" fat and the omega -3 fatty acids, in favour of the latter. The
intention was to follow the recommendations for healthy people, ≤ 30E% (40).
The role of commercial supplements
In the diet of many cancer patients, commercial supplements contribute a considerable
share of the energy and nutrient intake. In a review of randomised control trials
including oral supplements and/or dietary advice, the conclusion was that supplements
may have a more important role than dietary advice for the improvement of body
43
weight and energy intake (122). In the study by Evans et al. (44), patients in the
counselled group all had commercial supplements, and in Ovesen et al (123), patients
were offered commercial supplements if indicated. In these studies, the nutritional
support increased energy intake and influenced weight development (44,123). Less
weight loss was seen during the first 4 weeks in patients with lung cancer (44). In the
study by Ovesen et al (123) of patients with SCLC, ovarian or breast cancer, weight
increased more in the counselled group, but the difference was not statistically
significant after 5 months.
Commercial supplements were available to patients in all of the present studies. The
possibility to prescribe supplements to cancer patients with subscription was
introduced in Uppsala County during Study I. Members of the resource group
participated in the preparatory work for this. Only two patients received enteral
nutrition during the last month before they died (Study III).
However, too many patients do not take their supplements as prescribed, and they
must be encouraged and reminded to do so. An opportunity to taste a number of the
supplements before the prescription is likely to increase the probability of
consumption as recommended, although this has not been properly studied.
Patients and families benefit from practical advice about how to vary the supplements,
e. g. mixed with milk, cream, ice cream, fruit and berries. However, it appears
necessary to stress that the supplements are mainly intended to be supplements, and
the primary measure is to improve the intake of food and drinks, e.g. to choose more
energy dense alternatives, or to serve the meals at other times or in different ways.
44
The relation between weight development and dietary intake
In the present studies in which nutritional support was an intervention (Studies I, III
and V), a positive change in weight development was seen. In spite of the advice to eat
energy dense food, and to have many meals and snacks, the mean energy intake did
not increase to a great extent. The percentage of energy provided by fat, 38-42% in
Study I and 35-40% in Study III was in accordance with the recommended level in
energy dense food (100). In Study V the patients did not succeed to reduce the
proportion of fat as intended (mean intake 33-35%). However, on the FO regimen the
plasma levels of EPA and DHA still increased as expected.
Although most of the patients with GI cancer in Study III did not reach the energy
levels recommended for healthy people of the corresponding age (40), they did not
continue to lose weight. A possible reason for this may be that cancer patients have
lower energy requirements (35,124), and/or lower energy expenditure than healthy
peers due to a lower level of physical activity. Another possibility is that the energy
intake before inclusion in the studies was that low that even a modest increase of food
intake was enough to have a positive influence on the weight development. The
patients with SCLC increased their energy intake, but still continued to lose weight.
Presumably they had an increased energy need (37), and should have had a more
aggressive nutritional support, possibly including enteral nutrition, to stop their weight
loss. The lung cancer patients received intensive and frequently prolonged
chemotherapy with the aim to prolong survival and possibly cure some, whereas the
GI cancer patients generally received much less chemotherapy. In Study V the energy
provided by the fish oil probably contributed to the stabilisation of body weight.
45
The food at home
Support of and information to family members may improve the cancer patient's
dietary intake. Nutritional problems often cause anxiety in the family; to eat and drink
is fundamental to our daily life. Families and other caregivers need information, verbal
and in writing, on suitable messages, including the "consumed food is good food", and
how to best utilise commercial supplements. In Studies I, III and IV, the dietician had
continuous contact with the families, on the ward, at the out-patient clinic and by
telephone.
The food at the hospital
In order to facilitate for cancer patients to at least try to increase their energy intake,
there must be a possibility for them to get what they like to eat and drink at a time
when they want it. Thus, a great variety of food and drinks should be available at the
hospital. The hospital kitchen menu should include energy dense food, food of varying
consistency e.g. fluid, minced, purée, and cold and hot food. In addition, the ward
kitchen should offer a large selection of snacks, drinks, commercial supplements and
food like pancakes, meatballs, omelettes and soups.
The change of system for serving the food, which was implemented on the ward
during Study I, resulted in a more pleasant environment at the meals. The patients
could decide the components and the size of the portion at the actual time of the meal,
not the day before as in the standard serving system with ready-made trays. At
Christmas and Easter the staff and the dietician arranged meals with traditional food,
which the patients and the staff ate together.
46
Information and education to staff at the hospital and in home care
Actions aiming at an improved nutritional support are actually not complicated, but
they have to be performed, and thus some knowledge is required. Dieticians are
uniquely qualified to provide nutritional intervention in the form of diet instructions
and intensive nutritional support, but there is no theoretical reason to believe that other
professionals could not give dietary advice (122). However, nutrition is only a minor
part in the basic education of physicians and nurses. The possibility of a good
nutritional care of the patients increases with repeated information, education and
discussion concerning nutritional issues. The dietician meets the patient for dietary
recall and dietary advice during a relatively short period of time. The staff, on the
wards and in home care, has contact with the patients more frequently and should
provide the basic nutritional care.
In Studies I and III, there were extensive educational programs intended for
physicians, nurses, and assistant nurses. These were implemented in different ways.
The dietician had the main responsibility for the education in nutritional care.
Lectures, seminars, educational days and group discussions were used to cover
theoretical issues. On the wards there were practical training, teaching and discussions
in daily work. The home care nurses in Study III also had the possibility to meet the
dietician during problem-focused supervision, and to phone for consultation on
individual patients. It may be advantageous if other team members e.g.
physiotherapist, occupational therapist, social worker and dental hygienist, are also
invited to attend the education and information on nutrition. This was done in Studies I
and III. Patients tend to discuss their weight loss and other nutritional problem with
most staff involved in the care.
47
Weight development and the use of anti-cachectic drugs
The potential of omega-3 fatty acids and melatonin to reduce the level of cytokines,
involved in cachexia has been demonstrated in earlier studies in the form of
associations with weight gain, improvement in performance status, better appetite and
survival (87, 90-93). In Study V, these substances were used to explore the effect of
each during four weeks, and then their combination during a second period. The
included patients had advanced disease, and no further medical tumour controlling
treatment was available for most of them. The study was performed to find out if
patients would benefit by fish oil, melatonin and dietary advice. The FO and MLT
interventions were generally well tolerated. On FO the plasma level of fatty acids
changed in a manner similar to that of healthy individuals on a similar dose (117). This
suggests that a severe cancer-associated inflammatory state does not inhibit the fatty
acid response expected from high dose FO. A stabilisation was seen in the weight
development. Considering the weight loss of almost 3kg /month seen in weight losing
patients with pancreatic cancer receiving supportive care only (90), this could be
regarded as a positive effect. Given the results in earlier and in the present studies,
further explorations of the putative beneficial effects of FO and MLT are justified.
48
Nutritional support and cancer treatment
All nutritional interventions, particularly preventive ones, must be performed in close
collaboration with the treating physicians, recognising both population risk and
individual factors. Intensity and duration of treatments are examples of population
risks and certain concomitant diseases, special diets and social support are essentially
individual risks.
Many newly diagnosed cancer patients have lost weight prior to diagnosis. Once the
tumour growth is entirely eradicated, e.g. by surgical removal of a bowel cancer,
weight is usually regained and there is no need for any nutritional support. The
surgical trauma, e.g. a total gastrectomy in many patients with gastric cancer, may in
some patients cause longstanding problems requiring special attention. Radiotherapy
and particularly chemotherapy are frequently given during prolonged time periods.
Thus, these patients might be at risk for nutritional problems during many months.
Chemotherapy treatments and patient groups vary greatly with respect to risk for
nutritional problems. The SCLC patients in Study I were selected for nutritional
intervention in addition to all other interventions for this reason. However, patients
with breast cancer were not. During adjuvant chemotherapy the experience is rather
the opposite: namely that breast cancer patients frequently gain weight. This is
probably due to a hormonal influence by the medical therapy (125).
49
CONCLUSIONS
♦ Weight loss is related to quality of life, response to treatment and
survival.
Weight loss was shown to be associated with poor QoL, low performance status,
and less probability to respond to cytostatic treatment and poor survival in cancer
patients. The result of the present studies add further support to previous research
showing that weight loss is a risk factor of poor outcomes in cancer patients.
A routine where all patients are weighed at each visit at the out-patient clinic, at
admission on the wards and once a week during their hospital stay, would facilitate
an earlier discovery of patients at risk or already malnourished. Preferably this
should be the routine not only at the cancer clinics; weight loss might be a risk
factor in any patient.
♦ The PG-SGA turned out to be useful for identification of patients at risk
for malnutrition.
A more detailed assessment of nutritional status using a simple questionnaire, at
least in the weight losing patients, provides information useful for planning the
future nutritional care. In patients assessed as SGA B or C, nutritional actions
should be instituted such as a referral, if not already done, to a dietician.
50
♦ Patients benefit from dietary advice and other nutritional support.
It is possible for cancer patients to increase their dietary intake and in this way
improve weight development. In addition to dietary advice, often including
commercial supplements, directly to the patients, support and information to the
families, information to and education to staff should be included in nutritional
support. The practical teaching in daily practice used at the lung cancer ward and
the co-operation between the specialist clinics and the home care service can be
looked upon as good examples.
♦ Supplementation with fish oil and melatonin did result in weight
stabilisation.
In the cachectic cancer patient, good nutritional support and care does not seem to
be enough. In an exploratory trial, when fish oil and melatonin were used as
potential anti-cachectic drugs, there was a stabilisation of body weight
development. However, it is difficult to determine which of the interventions,
dietary advice, fish oil or melatonin, that had the strongest impact on weight.
Neither of the drugs had any systematic impact on the chosen markers for cachexia
development.
Considering the results of earlier studies and our experience in Study V, there does
not seem to be any reason to advice against the use of fish oil in patients who ask
about it. However, they should be advised to comply with the dose
recommendations from the manufacture. More knowledge on this issue can only be
provided by large randomised trials in homogenous patient groups.
51
ABBREVIATIONS
AA Arachidonic acid
APPR Acute phase protein response
BMI Body mass index
BW Body weight
CIPS Cancer inventory of problem situation
CRP C-reactive protein
DHA Docosahexaenoic acid
E% Energy percentage
EE Energy expenditure
EORTC The European organisation for research and treatment of cancer
EPA Eisosapentaenoic acid
FO Fish oil
GI Gastrointestinal
GR Group rehabilitation
IL-1 β Interleukin 1β
IL-6 Interleukin 6
IL-8 Interleukin 8
IPHC Intensified primary health care
IPS Individual psychological support
IS Individual support
Kcal Kilocalories
KPS Karnofsky performance status
MLT Melatonin
NNR Nordic nutrition recommendations
52
NS Nutritional support
P-prealb P-prealbumin
PG-SGA Patient generated subjective global assessment
PGE2 Prostaglandin E2
QoL Quality of life
RDA Recommended daily allowances
REE Resting energy expenditure
S-alb Serum-albumin
S-Hb Serum haemoglobin
S-LDH Plasma Lactate Dehydrogenase
SC Standard care
SCLC Small cell lung cancer
SGA Subjective global assessment
sIL-2r soluble Interleukin 2 receptor
S/N-C Survival/nutrition control group
SNR Swedish nutrition recommendations
SPG Study period group
TEE Total energy expenditure
TNF-α Tumour necrosis factor α
53
ACKNOWLEDGEMENTS
I wish to express my gratitude to all persons, who in different ways have supported me
during my graduate studies and in my work. In particular I would like to thank the
following persons:
Bengt Glimelius, my execellent supervisor, who with his apparently endless patience
always has supported me.
Per-Olow Sjödén, my co-tutor for all his advice in scientific and linguistic matters, and
for being a generous landlord at the Section for Caring Sciences
Birgitta Johansson for fruitful discussions on statistical and oenological questions.
All my other friends in the ”Support-Care-Rehabilitation” project, Katarina ,
Lena-Marie, Maria, Peter, Imke, Gunilla Ö, Gunilla B and Yvonne.
Colleauges and friends at "Plan1", Kristina, Mariannne H, Karin, Maria, Kerstin,
Camilla and Ulrika for support and cosy chats during lunch breaks.
Additional friends at the Section for Caring Sciences for creating a nice and inspiring
atmosphere.
All members of the staff on the former ward 40 C at the Lung Medicine Clinic, and
especially Enn Nou and Gunnilla Högman.
My friends and colleagues at Dietistenheten Karin, Birgitta, Mia, Eva, Sigrid and
Nina.
Rosa Lorentsson, for teaching me the advantage of cream, butter and sugar.
Inger Hjertström-Öst, who always has time to answer my questions and help me.
Didde Simonson Westerström for administrative support and pleasant chats.
Maria, Majlis, Rut, Britt Marie, who performed all the blood tests in the studies.
My dear husband Åke and my lovely daughter Helena for being patient with me when
I have spent more time with my Macintosh than with you.
54
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Appendix 1(4)
APPENDIX
Patient Generated Subjective Global Assessment.
Questions answered by the patient.
1. I am about..........cm tall
I weigh about............kg
A year ago I weighed about............kg
Six months ago I weighed about.........kg
During the past 2 weeks my weight has
decreased .........kg
not changed
increased ..........kg
2. I would rate my food intake during the past month (compared to my
normal) as
no change
more than usual
less than usual
much less than usual
taking only liquids
taking only nutritional supplements
really taking in very little of anything
73
Appendix 2(4)
3. Over the past 2 weeks I have had the following problems that keep me from
eating enough (check all that apply)
no problems
no appetite, just did not feel like eating
nausea
vomiting
diarrhoea
constipation
mouth sores
dry mouth
pain
thing taste funny or have no taste
smells bother me
other ……………………………………….
4. Functional capacity
Over the past month I would rate my activity as generally
normal, no limitations
not my normal self, but able to be up and about with fairly
normal activity
not feeling up to most things bur in bed less than half the day
able to do little activity and I spend most of the day in bed
pretty much bedridden
74
Appendix 3(4)
Questions answered by physician or dietician
5. Disease and its relation to nutritional requirements
Primary diagnosis...............................................
(stage if known.....................................)
Metabolic demand (stress) no stress low moderate high
6. Physical (0=normal, 1=mild, 2=moderate, 3=severe)
loss of subcutaneous fat (triceps, chest)
muscle wasting (quadriceps, deltoid)
ankle oedema sacral oedema ascites
7. SGA rating
A= well nourished
B = moderately (or suspected of being) malnourished
C = severely malnourished
Patient-Generated Subjective Global Assessment of Nutritional Status
F.D Ottery 1995
75
Appendix 4(4)
Guidelines.
Metabolic demand (stress).
May include: stress, tumour fever, depression, pain, fatigue, affect of the tumour,
treatment
Loss of subcutaneous fat.
Subjective impression by palpation
Muscle wasting.
Loss of bulk and tone detectable by palpation
Oedema.
Noted by inspection and palpation.
Ascites.
Noted by inspection and palpation.
SGA rating.
SGA A.
A nonfluid weight gain during the last 2 weeks, even if the net loss the last six months
was 5-10% and the patient had a mild loss of subcutaneous fat. Improvements e.g
better appetite.
SGA B
> 5% weight loss the last 2 weeks without stabilisation or weight gain,
definite reduction in dietary intake, mild loss of subcutaneous fat.
SGA C
Obvious signs of malnutrition eg severe loss of subcutaneous fat, muscle wasting and
often oedema, weight loss > 10 %
