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Supportive Care in Cancer
ISSN 0941-4355
Support Care Cancer
DOI 10.1007/s00520-018-4154-9
The effect of nabilone on appetite,
nutritional status, and quality of life
in lung cancer patients: a randomized,
double-blind clinical trial
Jenny G.Turcott, María del Rocío
Guillen Núñez, Diana Flores-Estrada,
Luis F.Oñate-Ocaña, Zyanya Lucia
Zatarain-Barrón, et al.
1 23
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ORIGINAL ARTICLE
The effect of nabilone on appetite, nutritional status, and quality of life
in lung cancer patients: a randomized, double-blind clinical trial
Jenny G. Turcott
1
&María del Rocío Guillen Núñez
2
&Diana Flores-Estrada
1
&Luis F. Oñate-Ocaña
3
&
Zyanya Lucia Zatarain-Barrón
1
&Feliciano Barrón
1
&Oscar Arrieta
1
Received: 18 December 2017 /Accepted: 5 March 2018
#Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract
Background Over one half of the patients diagnosed with advanced lung cancer experience anorexia. In addition to its high
incidence, cancer-induced anorexia promotes the development of the anorexia-cachexia syndrome, which is related to poor
clinical outcomes. Recently, drugs derived from cannabinoids, such as Nabilone, have been recognized for their appetite
improvement properties; however, clinical trials to support their use in cancer patients are necessary.
Methods This is a randomized, double-blind, placebo-controlled clinical trial to assess the effect of Nabilone vs. placebo on the
appetite, nutritional status, and quality of life in patients diagnosed with advanced Non-small cell lung cancer (NSCLC)
(NCT02802540).
Results A total of 65 patients from the outpatient clinic at the National Institute of Cancer (INCan) were assessed for eligibility
and 47 were randomized to receive Nabilone (0.5 mg/2 weeks followed by 1.0 mg/6 weeks) or placebo. After 8 weeks of
treatment, patients who received Nabilone increased their caloric intake (342-kcal) and had a significantly higher intake of
carbohydrates (64 g) compared to patients receiving placebo (p= 0.040). Quality of life also showed significant improvements
in patients in the experimental arm of the trial, particularly in role functioning (p= 0.030), emotional functioning (p=0.018),
social functioning (p= 0.036), pain (p= 0.06), and insomnia (p= 0.020). No significant change in these scales was seen in the
control group.
Conclusion Nabilone is an adequate and safe therapeutic option to aid in the treatment of patients diagnosed with anorexia.
Larger trials are necessary in order to draw robust conclusions in regard to its efficacy in lung cancer patients.
Keywords Anorexia .Orexigenic agent .Energy consumption .Lung cancer .Quality of life
Introduction
Lung cancer patients have the highest rate in cancer mortality
worldwide [1], with a poor prognosis and 16% of survival in
5years[2,3]. At least a half of the patients with advanced
non-small cell lung cancer (NSCLC) experience anorexia
(lack of appetite), and this number increases up to 80% as
disease progresses [4]. Anorexia is importantly related to a
reduced food intake, weight loss, and promotes the cancer
anorexia-cachexia syndrome (CACS) [5]. Patients who are
identified with anorexia at the time of cancer diagnosis should
be treated in a timely manner. Early intervention on patients
with anorexia can prevent the onset of CACS, which is a
recognized factor for poor prognosis, including a significant
decrease in overall survival (OS) and can worsen
chemotherapy-derived toxicity [6]; in addition, it is associated
with poor quality of life and has a negative impact on family
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00520-018-4154-9) contains supplementary
material, which is available to authorized users.
*Oscar Arrieta
ogar@unam.mx
1
Head of Thoracic Oncology Unit and Experimental Oncology
Laboratory, Instituto Nacional de Cancerología de México (INCan),
San Fernando #22, Col. Sección XVI, Tlalpan, 14080 México, D.F.,
Mexico
2
Pain Management Clinic, National Cancer Institute of Mexico
(INCan), CDMX, Mexico
3
Clinical Research Division, Surgery Division, National Cancer
Institute of Mexico (INCan), CDMX, Mexico
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https://doi.org/10.1007/s00520-018-4154-9
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members. Most patients with anorexia will further on develop
CACS, the treatment of which includes nutritional interven-
tion, physical activity, and pharmacological treatment [7].
Pharmacological intervention for CACS seeks to improve ap-
petite; decrease the inflammatory reaction, related to patient
prognosis; and promote anabolic metabolism [7–9]. In spite of
its impact in patient overall health and quality of life, a gold
standard for treating cancer-associated anorexia has not been
established, and the effectiveness of drugs remains controver-
sial or limited to a specific patient subgroup.
Drugs currently under use include megestrol acetate, which
increases appetite and weight gain, but its long-term use is
limited by the development of potentially serious side effects
such as thromboembolic phenomena, edema, and lower re-
sponse rate to chemotherapy and a trend for inferior survival
duration [10]. Other agents whose effectiveness has been test-
ed in NSCLC patients include anamorelin, which has been
shown to significantly improve Anorexia/Cachexia Scale
(AC/S) score and increase total weight and lean body mass
compared to patients assigned to placebo [11]. Anamorelin is
a ghrelin receptor agonist but is not readily available world-
wide. Other nutritional supplements have also been tested,
with limited results [12]. Cannabinoids have been suggested
to be a valuable treatment option for improving appetite in
patients with anorexia [13]. Among cannabinoids, dronabinol
has been found to have antiemetic properties and to stimulate
appetite. Several previous studies have shown dronabinol to
convey therapeutic benefits in cancer patients who have an-
orexia and weight loss. However, results have not been con-
clusive in regard to the mechanisms for appetite stimulation
and its impact on weight gain [14]. Nabilone (Cesamet®) is a
synthetic analogue of Δ-9 tetrahydrocannabinol (THC), and it
has been used in Western Europe and Canada for over 20 years
and is approved by the Food and Drug Administration for
chemotherapy-induced nausea and vomiting [15,16].
Nabilone presents several advantages compared to other can-
nabinoids, such as dronabinol. For example, nabilone has
higher bioavailability compared to dronabinol (95% vs. 10–
20%), presents a higher duration of action, and is not detected
on urine drug tests [17]. The orexigenic effects of THC occur
through the inhibition of leptin at the hypothalamic level, [15]
and also by palliating dysgeusia, a significant side effect in
patients receiving chemotherapy [13,18]. Although cannabi-
noidshavebeenassociatedwithappetitestimulation,noclin-
ical trials focused in lung cancer-related anorexia as a primary
objective have been conducted to date [16]. A relevant study
evaluated the effect of administering nabilone for the manage-
ment of pain and symptoms experienced by patients with ad-
vanced cancer. The patients receiving nabilone showed bor-
derline improvement in appetite compared with those not tak-
ing nabilone (p= 0.0516) [15]. Moreover, a pilot study in
cancer patients determined that delta-9-THC could improve
dysgeusia (p= 0.026), appetite (p = 0.05), and protein intake
(p= 0.008) and increase quality of sleep (p= 0.025) and relax-
ation (p= 0.045) in patients with chemosensory alterations.
However, another trial evaluated the administration of delta-
9-tetrahydrocannabinol in 65 patients and found a 58% in-
crease in appetite compared to 69% using placebo [19].
In this randomized, double-blind, placebo-controlled pilot
study, we sought to evaluate the effect of nabilone vs. placebo
in lung cancer patients diagnosed with anorexia using the AC/
S of the Functional Assessment of Anorexia Cachexia
Therapy (FAACT) tool [20].
Materials and methods
This was a randomized, double-blind, placebo-controlled pilot
study to evaluate the effect of nabilone vs. placebo during
8 weeks of treatment in stage III and IV NSCLC patients from
the outpatient clinic of the Thoracic Oncology Unit at the
Instituto Nacional de Cancerología (INCan) in México City.
The study received approval by the Institutional Review
Board and Ethic Committee (014/005/ICI)(CEI 883/14) and
was registered at Clinicaltrials.gov (NCT02802540).
Eligibility criteria
Patients diagnosed with histologically confirmed advanced
NSCLC, regardless of current therapeutic scheme, with a
good performance status (Eaestern Coperative Oncology
Group score [ECOG] 0–2), diagnosed with anorexia accord-
ing to the AC/S were screened for inclusion. The visual ana-
logue scale (VAS) for loss of appetite and weight loss were
registered. Patients were informed of the objective of the study
and were invited to participate and sign an informed consent
form. Exclusion criteria for this study included patients who
withdrew their informed consent and did not wish to continue
in this study, patients who only underwent the baseline eval-
uation and did not attend the rest of the follow-up, patients
who decided to stop taking the medication after they had
agreed to enter the study, patients with a known allergy and/
or contraindication for receiving cannabinoids, patients who
had previously received treatment with cannabinoids, and pa-
tients who had previously received any other pharmacological
treatment for anorexia.
Stratification and randomization
After baseline assessment, patients were randomized by the
protocol coordinator in a double-blind manner to receive cap-
sules for oral administration of 0.5 mg daily of nabilone or
placebo for 2 weeks, as administration of this agent must
initiate with an induction dose as per regulatory indication.
Subsequently the dose was increased to 1 mg daily for the
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next 6 weeks. Patients were evaluated at the time of inclusion,
and 4 and 8 weeks after randomization.
Nutritional assessment
The presence of anorexia was identified using the AC/S-12
section of the FAACT tool [20]; patient perception of loss of
appetite was evaluated using a unidirectional VAS. Body
weight and height were measured. The body mass index
(BMI) was calculated as body weight/height squared. A sub-
jective global assessment (PG-SGA) was used to assess and
classify patients as having moderate or severe
malnourishment (B or C) or as being well nourished (A).
Food intake was measured using the SNUT program, which
calculates calories, proteins, carbohydrates, fats, and
micronutrients, including iron and zinc [21].
Biochemical parameters
The biochemical data evaluation included an analysis of the
serum albumin level and a complete blood cell count. Venous
blood samples were drawn from patients after an overnight
fast. All laboratory values were determined using routine au-
tomated analyzers at the Department of Clinical Chemistry at
the INCan.
NLR was defined as absolute neutrophil count divided by
absolute lymphocyte count, whereas PLR was described as
absolute platelet count divided by absolute lymphocyte count.
NLR ≥5 and PLR ≥150 were considered to indicate systemic
inflammatory response (SIR) [22].
HRQL evaluation and toxicity
The Health-related quality of life (HRQL) evaluation was
assessed using the validated Mexican-Spanish version of the
European Organization for the Research and Treatment of
Cancer Quality of Life Questionnaires specific for cancer
and for LC (EORTC-QLQ-C30 and QLQ-LC13, respectively)
[23,24]. Scores for the multi-item functional, symptom scales
and the single-item scales were calculated using a linear trans-
formation of raw scores to produce a range from 0 to 100, as
described by EORTC. In this scale, the best score is 100 for
the global health status and functional scales, while scores
nearing 0 represent lesser symptoms. Chemotherapy toxicity
was evaluated using the Common Terminology Criteria for
Adverse Effects (CTCAE).
Statistical analysis
For descriptive purposes, continuous data were summarized as
arithmetic means and standard deviation (SD), whereas cate-
gorical variables were summarized as proportions. Square chi
and student t test were performed to analyze baseline
differences between groups. Among each group, differences
overtimewereanalyzedusingapairedttest for nutrimental
and biochemical variables (baseline–4 weeks, baseline–
8 weeks) and Friedman for Quality of life scales (baseline–
4weeks–8 weeks). Overall survival (OS) was defined as the
time from randomization until death or loss to follow up. OS
was analyzed using the Kaplan-Meier method, and compari-
sons among median values were performed using the Log-rank
test. A pvalue of 0.05 (two-sided) or lower was considered
significant. SPSS for MAC version 20 was employed to per-
form all analyses (IBM, Corp., Armonk, NY, USA).
Results
Participants
A total of 65 patients were evaluated at the National Cancer
Institute of Mexico to be included in this study, from
December 2013 to December 2015. Sixteen patients did not
meet the inclusion criteria, and 47 patients were randomized to
the experimental and control groups (Fig. 1). From the already
randomized patients, four never started treatments because of
an event of hospitalization after randomization, four died, and
six did not return for the complete evaluation (Fig. 1). Sixty-
four percent (n= 13) of patients in the placebo group and 68%
(n= 9) of patients in the experimental group completed the
8 weeks of follow-up. The loss of follow-up in the experimen-
tal and control groups was due to death (3 and 1, respectively)
and to deterioration in their medical condition (2 and 5, re-
spectively), both related to cancer (Fig. 1). Baseline differ-
ences among groups included a worse performance status
(p= 0.010), older age (p= 0.042), and greater weight loss in
the last 6 months (p= 0.032) for patients in the experimental
arm of the trial (Table 1).
At the 4-week evaluation, no statistically significant differ-
ences were found between the control and experimental
groups in regard to appetite and anthropometric and biochem-
ical variables (Supplementary Table 1).
At the 8-week evaluation, we did not find a statistically
significant difference when comparing the experimental and
control group in regard to appetite and anthropometric and
biochemical variables (Table 2). The appetite increase for each
group was close in magnitude, and the final change in the AC/
S score was similar between both arms of the trial (AC/S Δ8
vs. 8.4; p= 0.929). However, there was a statistically signifi-
cant improvement in VAS for the experimental group (p=
0.006), with the higher difference towards improvement be-
tween groups (Δ−1.1 control vs. −2.8 experimental, p=
0.219). The experimental group had a higher weight loss com-
pared to the control group (300 g); however, this difference
was not statistically significant when comparing both groups
(p=0.724)(Table3).
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In regard to biochemical parameters, patients in the exper-
imental group experienced a statistically significant decrease
in PLR when comparing baseline vs. 8-week value (Table 2).
Interestingly, patients with lower PLR (≤150 vs. > 150) had
better OS (12.6 vs. 20.6 months in patients with PLR > 150 vs.
PLR ≤150; p=0.034)(Fig.2).
In terms of nutritional consumption, patients in the exper-
imental group had a statistically significant difference in re-
gard to carbohydrate consumption compared to the control
group (Δ−42.4 g vs. 21.8 g control and experimental groups
respectively, p= 0.040) in the 8-week evaluation (Table 3).
The control group had a statistically significant decrease in
energy consumption (p= 0.041) and when comparing groups,
we found a difference in energy consumption of 342 kcal (Δ
−280 kcal control vs. 61.4 kcal experimental; p=0.123)
(Table 3) (Supplementary Fig. 1). Other differences in terms
of protein and fat intake can be consulted in Table 3.
Previously, it has been determined that anorexia can dictate
the types of foods preferred by patients, and therefore, its
treatment may reverse alterations in dietary preferences
[25,26].
The evaluation of HRQL showed that the experimental
group has an improvement in the functional scale (p=
0.030), emotional scale (p= 0.018), social scale (p=0.036),
pain (p=0.016),and insomnia (p= 0.020) at 8 weeks, while
the control group did not register any significant improvement
in relation to these HRQL scales (Table 4). Nonetheless, the
control group showed a significant reduction in appetite loss,
whereas the experimental group also shows a difference, al-
though this was only borderline significant (p= 0.060). In
regard to nausea and vomiting, the control group also showed
a significant improvement when comparing the baseline and
8-week evaluation (p= 0.043), but it is important to highlight
that the experimental group did not record any events of grade
3 or higher nausea after treatment had been administered (4-
and 8-week evaluation).
Discussion
This study compares nabilone and placebo in lung cancer-
associated anorexia. Both groups improved appetite according
Fig. 1 CONSORT diagram
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to the AC/S and VAS tools; however, the nutrimental con-
sumption and quality of life was considerably different when
taking into consideration the experimental and control groups
of our study. It is important to highlight that all participants
were initially screened for depression, and results between
groups showed no statistically significant difference; there-
fore, this important confounding factor in terms of appetite
is not present in our study [27].
Our findings support that treatment with nabilone in pa-
tients diagnosed with anorexia increases energy consumption,
specifically carbohydrates, and improves functional scales of
quality of life, pain, and insomnia.
Patients with CACS frequently report reduced appetite and
food intake [5]. However, there is an important proportion of
patients with anorexia who have not yet fully developed
CACS. It remains unclear up to this day what proportion of
Table 1 Baseline characteristics among nabilone and control group patients
Control
n=19
Mean ± SD
Experimental
n=14
Mean ± SD
pvalue
Sex Male
Female
4(21.1)
15 (78.9)
3(21.4)
11 (78.6)
1
Stage III
IV
Not available
4(21.1)
15 (78.9)
0(0)
9(64.2)
4(28.6)
1(7.2)
0.625
Chemotherapy line 1
2
≥3
Not available
6(31.6)
3(15.8)
10 (52.6)
0(0)
4(28.6)
3(21.4)
6(42.8)
1(7.2)
0.841
ECOG 0
1
2
0(0)
19 (100)
0(0)
0(0)
9(64.3)
5(35.7)
0.010
SGA A
B
C
0(0)
6(31.6)
13 (68.4)
0(0)
6(42.9)
8(57.1)
0.506
Anorexia (CTCAE) 19 (100) 14 (100)
Age years 52.6 ± 11.8 61.1 ± 10.6 0.042
Weight kg 49.5 ± 9.7 50.7 ± 9.9 0.720
BMI kg/m
2
21.1 ± 2.6 20.9 ± 3.5 0.852
Weight loss past6-months % 10 ± 4.6 14.8 ± 7.3 0.032
AC/S (FAACT) 16.8 ± 6.7 21.4 ± 6.3 0.060
VAS appetite loss cm 7.1 ± 2.1 8.1 ± 2.1 0.191
Appetite (QLQ-C30) 80 ± 24.5 90.4 ± 4.2 0.258
Energy intake Kcal/day 1216 ± 310.4 1126 ± 393 0.475
Proteins gr/day 37.9 ± 14 35.2 ± 12.3 0.577
Carbohydrates gr/day 179.5 ± 48 164.8 ± 60.8 0.448
Fats gr/day 43.3 ± 16 39.9 ± 16.2 0.559
Iron mg/day 6.7 ± 1.9 6.8 ± 2.4 0.914
HRQL global status 41.1 ± 30.5 52.3 ± 28.9 0.312
VA S p a i n 4 . 8 ± 3 5 ± 3 . 5 0 . 8 91
Albumin mg/dl 3.6 ± 0.4 3.5 ± 0.7 0.634
Hemoglobin g/dl 11.7 ± 2.3 12.5 ± 1.7 0.323
Platelets × 10
3
/μL 332.3 ± 143.4 321.08 ± 124.4 0.825
Leucocytes × 10
3
/μL 6.6 ± 4.2 7.7 ± 4.2 0.515
Lymphoc ytes × 10
3
/μL 1.2 ± 1 1.3 ± 0.4 0.805
Neutrophils × 10
3
/μL 5.1 ± 3.8 5.7 ± 4 0.681
NLR 5.4 ± 3.9 4.7 ± 3.6 0.611
PLR 335.1 ± 192.5 263.2 ± 113.4 0.255
SGA subjective global assessment, BMI body mass index, AC/S anorexia cachexia scale from the functional assessment of anorexia cachexia therapy
(FAACT) tool, VAS visual analogue scale, NLR neutrophils lymphocytes ratio, PLR platelet lymphocyte ratio, CTCAE common terminology criteria for
adverse event
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lung cancer-associated anorexia can be successfully treated,
and therefore the onset of CACS averted in these patients.
Studies such as the one we present build on the already
existing body of evidence in terms of the treatment options
available for cancer patients who experience anorexia.
Existing therapies aim to improve patient’s appetite and in-
crease food intake but must also have a specific safety profile
in order to be safely administered to population whose health
is deteriorated and who are receiving many different drugs.
In our study, patient self-perception of loss of appetite was
1.5 times better in patients receiving the experimental therapy
vs. the placebo group at the 4-week evaluation, although this
difference did not reach statistical significance, probably due
to a limited sample size. Another important observation relates
Table 2 Differences in appetite and anthropometric and biochemical variables after 8 weeks of treatment
Control
n=19
Experimental
n=14
p
AC/S Baseline
8weeks
Δ
p
19 ± 6.6
27 ± 7.6
8.07 ± 9.4
0.009
18 ± 3.9
26 ± 8.4
8.4 ± 9.4
0.028
0.929
VAS (visual analogue scale) Baseline
8weeks
Δ
p
6.5 ± 2.08
5.3 ± 3.04
−1.1 ± 3.7
0.300
9 ± 1.6
6.1 ± 3.1
−2.8 ± 2.3
0.006
0.219
Weight (kg) Baseline
8weeks
Δ
p
51.1 ± 9.4
50.06 ± 9.1
−1.09 ± 2.6
0.119
51.6 ± 11.37
50.2 ± 11.6
−1.4 ± 1.6
0.032
0.724
BMI (body mass index) Baseline
8weeks
Δ
p
21.3 ± 2.8
20.8 ± 2.8
−0.5 ± 1.2
0.111
21.2 ± 4.3
20.6 ± 4.3
−0.6 ± 0.7
0.029
0.854
Hemoglobin (mg/dl) Baseline
8weeks
Δ
p
11.9 ± 2.2
11.6 ± 1.6
−0.3 ± 2.1
0.559
13.3 ± 1.7
13.4 ± 1.9
0.1 ± 1.3
0.847
0.638
Platelets (× 10
3
/μL) Baseline
8weeks
Δ
p
342.6 ± 151.9
284.3 ± 114.9
−58.2 ± 140.6
0.131
364.1 ± 145.7
283.2 ± 55.7
−80.8 ± 123.7
0.135
0.720
Leucocytes (×10
3
/μL) Baseline
8weeks
Δ
p
6.4 ± 4.1
7.08 ± 2.4
0.6 ± 3.5
0.506
5.8 ± 2.7
7 ± 2.9
1.1 ± 3.7
0.434
0.737
Lymphoc ytes (×10
3
/μL) Baseline
8weeks
Δ
p
1.2 ± 1
1.2 ± 0.7
0.0 ± 0.9
0.979
1.3 ± 0.4
1.6 ± 0.3
0.3 ± 0.5
0.135
0.381
Neutrophils (×10
3
/μL) Baseline
8weeks
Δ
p
4.9 ± 3.9
5.2 ± 2.4
0.2 ± 3.2
0.752
4.04 ± 2.5
4.7 ± 3.03
0.7 ± 3.6
0.618
0.773
Albumin (mg/dl) Baseline
8weeks
Δ
p
3.6 ± 0.3
3.7 ± 0.4
0.05 ± 0.2
0.543
3.5 ± 0.6
3.8 ± 0.3
0.2 ± 0.3
0.140
0.209
NLR (neutrophils/lymphocytes ratio) Baseline
8weeks
Δ
p
5.3 ± 4.3
6.1 ± 6.2
0.7 ± 4.8
0.564
3.1 ± 1.9
3.1 ± 2.5
−0.0 ± 2.9
0.988
0.709
PLR (platelets/lymphocytes Ratio) Baseline
8weeks
Δ
p
315.5 ± 135.3
304.2 ± 318.5
−11.2 ± 289.3
0.882
295.9 ± 125.9
177.6 ± 51.1
−118.3 ± 117.8
0.038
0.361
pdifferences between groups
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to the fact that at 4 weeks post-treatment start, the mean AC/S
score for the experimental group was 26.4, while the diagnos-
tic cutoff for anorexia in this scale is 24, which would show
that on average, patients receiving nabilone averted an anorex-
ia diagnosis 4 weeks post-treatment, compared to the control
group who had an average AC/S score at 4 weeks of 23.6.
We identified several important issues throughout the
course of this study, specifically regarding the diagnostic cut-
off score for anorexia while using the AC/S tool. The
European Society for Clinical Nutrition and Metabolism
(ESPEN) has suggested that a score ≤24 when using the
AC/S is diagnostic of anorexia; however, in our practice,
many patients reported loss of appetite with a score > 24 using
the AC/S. As the proposed score of ≤24 was set as an arbitrary
cutoff point, and lacked clinical validation, we set out to val-
idate a specific cutoff point to diagnose anorexia in lung can-
cer patients. In a previous study, we had validated the Spanish
version of the FAACT tool [28] and following this validation,
we additionally report that a cutoff point of AC/S ≤32.5 for
anorexia diagnosis has a sensibility of 80.3% and a specificity
of 85%, and therefore is able to screen and identify patients
who are already experiencing anorexia, but in early stages,
and it is perhaps these early patients who would most benefit
from receiving a timely pharmacological intervention [29].
When taking into consideration that when using the AC/S
score a lower score represents higher-grade anorexia, the pa-
tients included in this pilot study are considered to have severe
anorexia (cutoff AC/S ≤24), and nonetheless, they still
showed a reversible effect when treated with nabilone.
Patients in the experimental arm of this trial consumed 300
more kcal compared to the placebo group, and importantly,
many of these calories came from a higher carbohydrate in-
take in these patients; in this case, it is important to highlight
that 342 cal represent an important proportion of the calories
included in the daily intake of cancer patients.
Patients in the experimental group not only avoided a re-
duction in energy, carbohydrates, and fat consumption but
increased intake in all the previously mentioned parameters.
It is likely that because of the small sample size included, the
differences between groups in terms of energy, proteins, fats,
and iron did not reach statistical significance. Although, we do
observe energy and fats were significantly reduced in the con-
trol group, compared to the experimental group, which
showed improvement. It is important to mention that any
pharmacological therapy prescribed must be granted along
Table 3 Energy intake evaluation in control and experimental groups, differences in 8 weeks
Control
n=19
ΔExperimental
n=14
Δp
Energy intake
Kcal/day
Baseline
8 weeks
p
1246.1 ± 316.5
965.3 ± 294
0.041
−280.8 ± 420 1120 ± 310.5
1181.5 ± 471
0.748
61.4 ± 553 0.123
Proteins
(gr/day)
Baseline
8 weeks
p
38 ± 14.4
30.3 ± 15.7
0.226
−7.6 ± 20.6 35.4 ± 11.7
33.1 ± 10.5
0.705
−2.3 ± 18.1 0.551
Carbohydrates
(gr/day)
Baseline
8 weeks
p
192.8 ± 40.5
150.3 ± 49.5
0.041
−42.4 ± 63.7 166.4 ± 46.4
188.2 ± 69.6
0.370
21.8 ± 68.9 0.040
Fats
(gr/day)
Baseline
8 weeks
p
41.5 ± 16.9
29.4 ± 12.6
0.051
−12.07 ± 19 38.9 ± 15.8
40.8 ± 19.5
0.844
1.9 ± 28.5 0.193
Iron
(mg/day)
Baseline
8 weeks
p
7.1 ± 1.6
5.9 ± 2.6
0.288
−1.1 ± 3.3 7.1 ± 1.9
7.4 ± 2.7
0.747
0.3 ± 2.9 0.319
pdifferences between control and experimental group 8 weeks post-randomization
Fig. 2 Overall survival according to PLR
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with the appropriate nutritional care; in fact, it is likely that
many of the improved parameters in the control group of our
study might be related to the constant nutritional follow-up
and guidance to which they were subjected, identical to the
experimental group. The target of anorexia treatment must
therefore be viewed as a complementary strategy in which
the increase of food intake must be balanced, with an adequate
proportion of carbohydrates, proteins, and fats.
Another aspect evaluated in this study is the pro-
inflammatory factors produced by the tumor cells, which
likely impact the onset and history of cachexia. Some relevant
and easily accessible parameters to measure, as they are rou-
tinely tested in cancer patients, include the NLR, PLR, and C-
reactive protein. NLR ≥5, PLR ≥150, and CPR above
3.9 mg/dl have been considered indicators of the SIR, which
may contribute to the progressive decline in nutritional and
functional status associated with a poor prognosis and OS in
patients with advanced-stage NSCLC [26]. The present study
shows that PLR was significantly reduced in the experimental
group of this trial, and moreover, all patients with a PLR ≤
Table 4 HRQL differences between control and experimental group 8 weeks post-treatment
Control
n=19
Experimental
n=14
Global health status/QoL Baseline
4weeks
8weeks
p
47.4 ± 28
58.3 ± 15.7
60.8 ± 25.7
0.307
50 ± 32.2
61.1 ± 13.8
52.7 ± 31.4
0.755
Physical functioning Baseline
4weeks
8weeks
p
55.3 ± 27.2
60.6 ± 24.6
62 ± 28.4
0.490
52.5 ± 16.4
51.8 ± 27.4
56.2 ± 26.8
0.296
Role functioning Baseline
4weeks
8weeks
p
46.6 ± 39.9
41.6 ± 29.6
53.3 ± 36.6
0.325
24 ± 25.1
61.1 ± 36.3
55.5 ± 39.9
0.030
Emotional functioning Baseline
4weeks
8weeks
p
64.9 ± 20.7
78.3 ± 21.9
76.6 ± 17.4
0.227
62 ± 19.1
78.7 ± 9.4
72.2 ± 21.2
0.018
Cognitive functioning Baseline
4weeks
8weeks
p
79.9 ± 28.1
83.3 ± 20.7
85 ± 14.5
0.593
61.1 ± 25
62.9 ± 32
62.9 ± 20
1
Social functioning Baseline
4weeks
8weeks
p
58.3 ± 41.7
65 ± 32.8
56.6 ± 33.5
0.428
35.1 ± 30.5
59.2 ± 37.3
70.3 ± 28.5
0.036
Fatigue Baseline
4weeks
8weeks
p
65.5 ± 25.3
45.5 ± 27.9
49.9 ± 26.3
0.149
56.7 ± 33
44.44 ± 31.4
49.3 ± 28.9
0.695
Nausea and vomiting Baseline
4weeks
8weeks
p
31.6 ± 18.3
16.6 ± 15.7
20 ± 31
0.043
33.3 ± 38.1
16.6 ± 14.4
27.7 ± 25
0.756
Pain Baseline
4weeks
8weeks
p
54.9 ± 33.3
41.6 ± 34.4
48.3 ± 35.5
0.356
50 ± 38.1
11.1 ± 11.7
37 ± 29.7
0.016
Appetite loss Baseline
4weeks
8weeks
p
76.6 ± 22.4
46.6 ± 28.1
49.9 ± 45.1
0.014
92.5 ± 22.2
51.8 ± 44.44
62.9 ± 30.9
0.060
Insomnia Baseline
4weeks
8weeks
p
43.2 ± 35.3
43.3 ± 35.3
33.3 ± 15.7
0.764
70.3 ± 30.9
33.3 ± 40.8
29.6 ± 35.1
0.020
pdifferences between groups
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150 at the 8-week evaluation have an OS which is 8 months
longer compared to patients with a PLR > 150.
In terms of HRQL, relevant differences were observed
between groups. The experimental group showed im-
provement in the role functioning scale, emotional func-
tioning scale, and social functioning scale; all of them
strongly related to eating behavior. Likewise, significant
reduction in pain and insomnia was observed in the
nabilone group vs. control group. The role of cannabi-
noids in terms of quality of life has been controversial.
In a previous study for patients with head and neck can-
cers treated with radiotherapy, those receiving nabilone
did not show a significant improvement compared to pla-
cebo in terms of relieving symptoms like pain (p=
0.6048), nausea (p= 0.7105), loss of appetite (p=
0.3295), weight (p= 0.1454), mood (p= 0.3214), and
sleep (p= 0.4438) [30]. On the other hand, a retrospective
study evaluated the effect of nabilone treatment in 139
cancer patients in palliative care. Of these patients, 82
were prescribed nabilone and were compared to those
who had not taken the drug. Nabilone-treated patients
experienced significant reduction in pain (p< 0.001) and
remained stable in terms of drowsiness, tiredness, appe-
tite, and well-being ESAS scores, compared to the non-
nabilone group [31]. Patients taking nabilone in the pres-
ent study had a significant improvement in terms of pain
at the administered dose of 1 mg/day for 8 weeks accord-
ing with quality of life perception of patients, an impor-
tant change achieved with a small dose. Nausea, one of
the principal reasons for prescribing nabilone, did not
show a significant improvement in our experimental
group, although CTCAE grade 3 nausea was only ob-
served in the placebo group, while the experimental group
reported only grade 2 or less events at 8 weeks post-treat-
ment. Nonetheless, it is important to mention that the
maximum dose of nabilone prescribed for nausea is
6 mg/day, which is higher than our experimental dose.
This study exposes the potential improvement effect in
quality of life in lung cancer patients undergoing either che-
motherapy or targeted therapy, for which it is known that
nutritional status greatly affects efficacy and toxicity profile
[9,32]. Moreover, the side effects of cannabis are generally
tolerable and short lived [16]. One of the most expected side
effects from nabilone is somnolence, which in the present
study was significantly beneficial to balance the insomnia re-
ported in the experimental group.
We are aware that the study findings are limited by several
factors. One is the small sample size, which because of the
nature of this study as a pilot did not allow for greater patient
recruitment. On the other hand, there are some differences
between the baseline characteristics of our patient population;
however, it is important to observe that these changes favor
the control group, who were slightly younger, had a better
performance status, and had a lower weight loss in the last
6months.
Future considerations should take into account the time
since the start of anorexia, because of the adaptive behavior
that can be crucial for cannabinoid effect and which might
explain why the experimental group, which probably had an-
orexia for a longer period of time, did not avoid weight loss at
8 weeks post-treatment.
The current findings from this pilot study build on the
existing body of evidence in regard to the use of pharmaco-
logic therapy for the treatment of anorexia in cancer patients.
It is the first trial to explore the effects of nabilone in lung
cancer-related anorexia. Although the study presents several
limitations, the results described warrant the future develop-
ment of larger studies. In addition, an important conclusion
supported by this study is the unequivocal need to provide
cancer patients with timely and thorough nutritional evalua-
tions and to follow their status throughout disease course. The
future of the multidisciplinary approach to the management of
cancer patients must therefore not overlook the important role
of nutrition in the quality of life and outcomes of cancer
patients.
Funding Nabilone and placebo were donated by vealent pharmaceutical
without any further participation in the trial.
Compliance with ethical standards
Conflict of interest statement The authors declare that they have no
conflict of interest.
Ethical approval All procedures performed in studies involving human
participants were in accordance with the ethical standards of the institu-
tional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
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