Nutritions
Nutritions
Nutritions
Abstract
Objective: We tested the effect of dietary advice dedicated to increase intake in older patients at risk for malnutrition during
chemotherapy, versus usual care, on one-year mortality.
Method: We conducted a multicentre, open-label interventional, stratified (centre), parallel randomised controlled trial, with
a 1:1 ratio, with two-year follow-up. Patients were aged 70 years or older treated with chemotherapy for solid tumour and at
risk of malnutrition (MNA, Mini Nutritional Assessment 1723.5). Intervention consisted of diet counselling with the aim of
achieving an energy intake of 30 kCal/kg body weight/d and 1.2 g protein/kg/d, by face-to-face discussion targeting the
main nutritional symptoms, compared to usual care. Interviews were performed 6 times during the chemotherapy sessions
for 3 to 6 months. The primary endpoint was 1-year mortality and secondary endpoints were 2-year mortality, toxicities and
chemotherapy outcomes.
Results: Between April 2007 and March 2010 we randomised 341 patients and 336 were analysed: mean (standard
deviation) age of 78.0 y (4?9), 51.2% male, mean MNA 20.2 (2.1). Distribution of cancer types was similar in the two groups;
the most frequent were colon (22.4%), lymphoma (14.9%), lung (10.4%), and pancreas (17.0%). Both groups increased their
dietary intake, but to a larger extent with intervention (p,0.01). At the second visit, the energy target was achieved in 57
(40.4%) patients and the protein target in 66 (46.8%) with the intervention compared respectively to 13 (13.5%) and 20
(20.8%) in the controls. Death occurred during the first year in 143 patients (42.56%), without difference according to the
intervention (p = 0.79). No difference in nutritional status changes was found. Response to chemotherapy was also similar
between the groups.
Conclusion: Early dietary counselling was efficient in increasing intake but had no beneficial effect on mortality or
secondary outcomes. Cancer cachexia antianabolism may explain this lack of effect.
Trial Registration: ClinicalTrials.gov NCT00459589
Citation: Bourdel-Marchasson I, Blanc-Bisson C, Doussau A, Germain C, Blanc J-F, et al. (2014) Nutritional Advice in Older Patients at Risk of Malnutrition during
Treatment for Chemotherapy: A Two-Year Randomized Controlled Trial. PLoS ONE 9(9): e108687. doi:10.1371/journal.pone.0108687
Editor: Vincent Wong, The Chinese University of Hong Kong, Hong Kong
Received June 19, 2014; Accepted August 22, 2014; Published September 29, 2014
Copyright: 2014 Bourdel-Marchasson et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its
supporting information files.
Funding: This work was supported by the National Hospital Program of Clinical Research (Programme Hospitalier de Recherche Clinique 2006) (46%), La Ligue
contre le cancer (52%) and AMGEN (2%) and sponsored by the university hospital of Bordeaux (CHU Bordeaux). The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* Email: isabelle.bourdel-marchasson@chu-bordeaux.fr
Study design
Introduction
Weight loss in patients with cancer has long been linked to poor
prognosis [1]. It is therefore recommended to assess nutritional
status in patients undergoing nonsurgical oncologic treatment
[2,3]. Dietary counselling has been proposed in malnourished
patients with gastrointestinal cancers during chemotherapy
treatment [4].
A randomised controlled trial of a nutritional intervention was
conducted in 358 adults with weight loss and treated with
chemotherapy for metastatic or locally advanced digestive or nonsmall cell lung cancer [5]. The aim was to assess the effects of
nutritional advice and the prescription of an oral nutritional
supplement, either alone or combined for 6 weeks. None of the
interventions produced any benefit on outcomes including oneyear mortality and quality of life. The lack of effect of the
interventions may be due to the fact that cancers were advanced in
this study. Another similar trial of dietary support during 12 weeks
of chemotherapy reported no benefit in 192 patients with nonsmall-cell lung and colon cancer [6]. A meta-analysis of nutritional
intervention trials in cancer patients in very heterogeneous
situations (nutrition, cancer, treatments) did not show any benefit
of these interventions on mortality [7].
All these studies involved adult populations but without any
specific analysis of older patients. Nevertheless, cancers are more
and more frequent in older people and in 2005 it was estimated
that 56% of new cancers occurred in people older than 65 y [8].
One-year mortality increased by two-fold in older patients with
cancer undergoing chemotherapy who were malnourished or at
risk of malnutrition according to the MNA (Mini Nutritional
Assessment) [9]. Very few patients were malnourished (3 out of
202) so the relationships mainly concerned those at risk. In a
similar study including more malnourished patients (MNA,17,
13.8%), the relative risk (RR) of one-year mortality was higher
(2.77) for those with an MNA,24 [10]. This suggests an effect
related to the severity of nutritional impairment according to the
MNA. This specific tool for older patients includes items directly
associated to nutrition, such as anthropometric measures and
nutritional intake, together with health-related quality of life
measures such as comorbidities, mental health, autonomy and
subjective health [11], was shown correlated with cancer cachexia
features [12] and was one of the independent predictor for
chemotherapy toxicity [13]. MNA is thus the consensual tool to
assess malnutrition in older patients with cancer [3,14]. In older
patients, the increased risk of mortality associated with a lower
MNA score may be due to factors other than cancer. Thus,
nutritional support targeted on gerontological assessment may
better address the needs of older patients with cancer [15]. No
clinical trial has yet tested the effect of nutritional intervention in
older patients with cancer who were malnourished or at risk of
malnutrition according to the MNA scale.
In the present randomised clinical trial involving older patients
at risk of malnutrition, we assessed the effect of dietary counselling
implemented from the start of chemotherapy for solid tumours
and lymphoma on one-year and subsequent mortality and on
severe toxicities.
Patient selection
Patients older than 70 y with lymphoma or carcinoma with an
indication of chemotherapy and a Karnofsky index higher than
50% were screened for participation. Eligible carcinomas were
from the colon, stomach, pancreas and biliary tract, ovary,
prostate, bladder, and lung. Lymphoma types were any B cell
lymphoma, any T lymphoma, low malignancy lymphomas such as
follicular, lymphoplasmacytic, lymphocytic, mantle, MALT, and
other marginal zone lymphoma. Patients with a carcinoma of
unproven origin but compatible with any tumour in the abovementioned list could be included if a chemotherapy was planned.
Methods
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Protocol S1.
Study design
Introduction
Weight loss in patients with cancer has long been linked to poor
prognosis [1]. It is therefore recommended to assess nutritional
status in patients undergoing nonsurgical oncologic treatment
[2,3]. Dietary counselling has been proposed in malnourished
patients with gastrointestinal cancers during chemotherapy
treatment [4].
A randomised controlled trial of a nutritional intervention was
conducted in 358 adults with weight loss and treated with
chemotherapy for metastatic or locally advanced digestive or nonsmall cell lung cancer [5]. The aim was to assess the effects of
nutritional advice and the prescription of an oral nutritional
supplement, either alone or combined for 6 weeks. None of the
interventions produced any benefit on outcomes including oneyear mortality and quality of life. The lack of effect of the
interventions may be due to the fact that cancers were advanced in
this study. Another similar trial of dietary support during 12 weeks
of chemotherapy reported no benefit in 192 patients with nonsmall-cell lung and colon cancer [6]. A meta-analysis of nutritional
intervention trials in cancer patients in very heterogeneous
situations (nutrition, cancer, treatments) did not show any benefit
of these interventions on mortality [7].
All these studies involved adult populations but without any
specific analysis of older patients. Nevertheless, cancers are more
and more frequent in older people and in 2005 it was estimated
that 56% of new cancers occurred in people older than 65 y [8].
One-year mortality increased by two-fold in older patients with
cancer undergoing chemotherapy who were malnourished or at
risk of malnutrition according to the MNA (Mini Nutritional
Assessment) [9]. Very few patients were malnourished (3 out of
202) so the relationships mainly concerned those at risk. In a
similar study including more malnourished patients (MNA,17,
13.8%), the relative risk (RR) of one-year mortality was higher
(2.77) for those with an MNA,24 [10]. This suggests an effect
related to the severity of nutritional impairment according to the
MNA. This specific tool for older patients includes items directly
associated to nutrition, such as anthropometric measures and
nutritional intake, together with health-related quality of life
measures such as comorbidities, mental health, autonomy and
subjective health [11], was shown correlated with cancer cachexia
features [12] and was one of the independent predictor for
chemotherapy toxicity [13]. MNA is thus the consensual tool to
assess malnutrition in older patients with cancer [3,14]. In older
patients, the increased risk of mortality associated with a lower
MNA score may be due to factors other than cancer. Thus,
nutritional support targeted on gerontological assessment may
better address the needs of older patients with cancer [15]. No
clinical trial has yet tested the effect of nutritional intervention in
older patients with cancer who were malnourished or at risk of
malnutrition according to the MNA scale.
In the present randomised clinical trial involving older patients
at risk of malnutrition, we assessed the effect of dietary counselling
implemented from the start of chemotherapy for solid tumours
and lymphoma on one-year and subsequent mortality and on
severe toxicities.
Patient selection
Patients older than 70 y with lymphoma or carcinoma with an
indication of chemotherapy and a Karnofsky index higher than
50% were screened for participation. Eligible carcinomas were
from the colon, stomach, pancreas and biliary tract, ovary,
prostate, bladder, and lung. Lymphoma types were any B cell
lymphoma, any T lymphoma, low malignancy lymphomas such as
follicular, lymphoplasmacytic, lymphocytic, mantle, MALT, and
other marginal zone lymphoma. Patients with a carcinoma of
unproven origin but compatible with any tumour in the abovementioned list could be included if a chemotherapy was planned.
Methods
The protocol for this trial and supporting CONSORT checklist
are available as supporting information; see Checklist S1 and
Protocol S1.
Usual Care
N = 167
N = 169
20.4 (2.1)
20.1 (2.0)
78.3 (4.7)
77.7 (5.2)
54.5 (91)
47.9 (81)
71.6 (88)
78.4 (91)
Colon
19.2 (32)
25.6 (17)
Stomach
8.4 (14)
6.5 (11)
17.4 (29)
19.7 (33)
10.8 (18)
10.1 (17)
Prostate
5.4 (9)
2.4 (4)
Cancer % (n)
Bladder
7.8 (13)
4.2 (7)
Ovary
7.8 (13)
7.1 (12)
Breast
7.2 (12)
9.5 (16)
Lymphoma
16.2 (27)
13.7 (23)
None
30.0 (42)
35?6 (52)
8.6 (12)
8.2 (12)
40?7 (11)
57.1 (12)
83.2 (139)
84.6 (143)
28.6 (7.9)
28.9 (6.6)
1.6 (1.9)
1.6 (2.5)
12.0 (1.6)
11.8 (1.7)
36.8 (6.2)
36.9 (6.9)
34.7 (64.7)
34.1 (42.2)
the advice to each patient. The eight dietary cards addressed the
issues of: 1-dietary balance, 2-loss of appetite and enrichment, 3diarrhoea and constipation, 4-nausea and vomiting, 5-taste
disturbances, 6-oral pain and feeling of dryness, 7- swallowing
disorders, 8- diabetes. Dietary advice was complemented by
prescription of an oral supplement if pertinent in order to increase
intake. Six face-to-face visits were planned during chemotherapy
sessions and contact was made by phone in the event of an interval
between visits longer than two weeks due to the schedule of the
chemotherapy. Intervention lasted 3 to 6 months according to the
chemotherapy schedule of each patient. All study dieticians
received training for the study, which was also given if a new
dietician entered it. The duration of the intervention was 3 to 4
months according to the duration of chemotherapy. None of the
staff in cancer treatment centres were aware of the content of the
nutritional intervention.
Intervention
The Usual Care group (UC) received the nutritional care
routinely given in the cancer treatment settings and there were no
restrictions for dietary advice, oral supplements or prescription of
artificial nutrition. The Usual Care+Nutritional Intervention
(UC+NI) group received usual care and nutritional intervention.
Nutritional intervention began the first day of chemotherapy.
The study dietician, who did not belong to the staff of the cancer
treatment setting, provided dietary advice with the aim of
achieving an energy intake of 30 kCal/kg body weight/d and
1.2 g protein/kg/d [2]. Counselling was based on face-to faceinterviewing and dietary advice cards, and involved caregivers or
relatives if possible [16]. Actual dietary intake and gerontological
assessment routinely applied [15] were taken into account to adapt
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Statistics
Analyses were performed on an intention-to-treat basis.
Comparisons of dietary intake between groups were performed
using a mixed linear model accounting for repeated measures. The
Kaplan-Meier method was used to estimate survival probabilities
and mortality was compared using the Wald Chi2 test in a Cox
model adjusted on the recruiting centre of the participants.
Proportions were used to describe qualitative variables of the
secondary outcomes. Comparisons were made with the Chi2 test.
For the outcomes that were recorded at several visits such as
infections, the outcome was considered absent when the data was
not available in the main analysis. In a robustness analysis, we used
the missing = failure strategy. Quantitative variables were described with mean and standard deviation (SD) or Inter-Quartile
Interval (IQR) and compared using Students t test or the
Wilcoxon test according to the distribution of the analysed
variable.
Results
Patient flow
Among 771 screened patients, 341 were randomized in the trial
(Figure 1) and 336 were analyzed: mean (standard deviation, SD)
age 78.0 y (SD 4.9), 51.2% male, mean MNA 20.2 (SD 2.1).
Distribution of cancer types was similar in the two groups; the
most frequent were colon (22.4%), lymphoma (14.9%), lung
(10.4%) and pancreas (17.0%). Chemotherapy was first line in
83.9%. The trial was stopped before full recruitment at the end of
the inclusion period due to an insufficient rate of inclusions. The
slow recruitment was attributed to the existence of competitive
trials for chemotherapy agents. The resulting power of the analysis
was estimated 40% instead of 80% to detect a one-year mortality
difference of 10% or was 80% to detect a 15% difference between
the two groups. Among patients identified as eligible, reasons for
non-inclusion were mainly chemotherapy treatments already
started. Five more subjects were excluded from the analyzed
sample due to one withdrawal of consent and 4 major deviations
from the eligibility criteria in the UC group (head and neck
tumour and chronic lymphatic leukaemia, or 5th line of
chemotherapy). Five patients with minor eligibility deviation
(MNA,17 and one.23?5 and two with cardia cancer or
endocrine carcinoma of the pancreas) were kept in the analysed
sample after scientific committee approval. The resulting analyzed
sample included 336 subjects. Groups were balanced for age, sex
ratio, cancer characteristics, routine biochemical analyses and
blood cell count (Table 1). Two participants from the UC+NI
group refused to continue the intervention during the follow-up
but were followed up for mortality. In the UC+NI group 877
dietician-visits were performed in relation to 990 planned visits so
compliance with the intervention was estimated at 88.6%. There
were also 450 phone contacts. None of the participants were lost to
follow-up.
Figure 2. Dietary intake the day before each cycle during the
chemotherapy period. Data are presented as mean and 95% CI, or
proportion. Total dietary intake was analyzed with mixed models:
increase of total intake at the second visit in both groups (UC+NI, P,
0.0001; **UC, P = 0.02), with higher increased in UC+NI compared to UC,
P,0.01.
doi:10.1371/journal.pone.0108687.g002
Outcomes
The main outcome was one-year mortality recorded in centres.
Causes of death were recorded. General practitioners and patients
relatives were contacted if needed.
Chemotherapy management (dosage, changes and arrest), grade
34 toxicities including severe infections, weight changes,
prescription of enteral or parenteral nutrition, and hospitalization
for reasons other than chemotherapy were considered as
secondary outcomes. These data were collected by investigators
during the chemotherapy period. Two-year mortality was also
assessed.
Dietary intake
The mixed model was applied in 1248 records, corresponding
to 310 patients. At baseline, dietary intake was higher in the UC+
NI group compared to the UC group (difference of 178 kcal/day,
p,0.01). In both groups, dietary intake increased between visit 1
and visit 2 (UC+NI+328 kcal/day, p,0.0001; UC+132 kcal/day,
p = 0.02) but the difference was higher in the UC+NI group than
in the UC group (p,0.01) (Figure 2). At the visit 2, 57 (40.4%)
4
Figure 3. Two-year mortality according to groups UC and UC+NI. N = 336. Comparisons were performed with Cox model adjusted on
recruiting centres.
doi:10.1371/journal.pone.0108687.g003
Outcomes
One-year and two-year mortality were similar in both groups
(Figure 3, respectively R = 1.1, 95%CI = 0.81.5, p = 0.74, and
RR = 1.1, 95%CI = 0.91.5, p = 0.37). The main declared cause of
death was cancer disease (Table 2). There was no difference in
distribution of cause of death according to the groups. There was
no lost of follow-up patient for the main outcome.
Chemotherapy management and outcomes were similar in both
groups (Table 2). There were more UC patients with grade 34
infections than UC+NI ones (Table 2, p = 0.03). However, a
robustness analysis was performed due to the existence of missing
data and did not confirm the difference in the incidence of severe
infections. The rate of weight change and other secondary
outcomes were similar in both groups.
Discussion
This large randomised controlled trial investigated the effect of
nutritional support in older patients treated by chemotherapy for
cancer. Despite an increase in dietary intake that was higher in
patients with dietary counselling, no improvement was noted in
one- and two-year mortality in older subjects at risk of
malnutrition and undergoing chemotherapy.
However, a lower rate of serious infections during chemotherapy was observed. This result should be interpreted with caution
as it was not confirmed by the robustness analysis. A decreased
rate of severe infections may have favourably impacted the
prognosis but this event was relatively rare. The potential
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Usual Care
N = 167
N = 169
41.3 (69)
43.8 (74)
0.74
62.9 (105)
68.0 (115)
0.37
3.7 (4)
6.4 (7)
18.8 (6)
30.2 (13)
Stomach
50.0 (7)
54.5 (6)
62.1 (18)
66.7 (22)
77.8 (14)
76.5 (13)
Prostate
22.2 (2)
75.0 (3)
Bladder
53.8 (7)
57.1 (4)
Ovary
15.4 (2)
8.3 (1)
Breast
33.3 (4)
50.0 (8)
Lymphoma
33.3 (9)
17.4 (4)
40.6 (13)
48.8 (21)
Stomach
78.6 (11)
81.8 (9)
75.9 (22)
87.9 (29)
94.4 (17)
94.1 (16)
Prostate
88.9 (8)
100.0 (4)
Bladder
84.6 (11)
71.4 (5)
Ovary
15.4 (4)
41.7 (5)
Breast
58.3 (7)
62.5 (10)
Lymphoma
44.4 (12)
60.9 (14)
89.9 (62)
86.5 (64)
Chemotherapy toxicities
2.9 (2)
5.4 (4)
Other
7.2 (5)
8.2 (6)
93.3 (98)
90.4 (104)
Chemotherapy toxicities
1.9 (2)
3.5 (4)
Other
4.8 (5)
6.1 (7)
93.3 (98)
90.4 (104)
Chemotherapy toxicities
1.9 (2)
3.5 (4)
Other
4.8 (5)
6.1 (7)
65.0 (106)
64.8 (107)
0.97
62.0 (101)
64.2 (106)
0.67
0.39
11.1 (16)
7.0 (10)
Partial remission
23.6 (34)
30.8 (44)
Stabilization
40.3 (58)
40.6 (58)
Progression
25.0 (36)
21.7 (31)
24.0; 1
25.0; 1
57.7 (75)
56.9 (74)
28.0; 1.4
27.6; 3.0
0.59
0.59
Table 2. Cont.
Usual Care
N = 167
N = 169
6.0 (9)
5.6 (8)
0.87
10.4 (7)
4.2 (7)
0.03
Hospitalisation, % (n)
34.4 (56)
29.1 (48)
0.31
9.2 (15)
5.5 (9)
0.19
doi:10.1371/journal.pone.0108687.t002
Supporting Information
Consort S1 INOGAD Consort.
(DOC)
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Acknowledgments
(DOC)
(DOC)
Author Contributions
(PDF)
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