The use of steroids in the management of inoperable intestinal

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Palliative Medicine 2000; 14: 3–10
The use of steroids in the management of inoperable
intestinal obstruction in terminal cancer patients:
do they remove the obstruction?
G Laval Medecin, Unité de Recherche et de Soutien en Soins Palliatifs, CHU Grenoble, J Girardier
Chirurgien, Unité de Soins Palliatifs la Mirandière, Quétigny, JM Lassaunière Medecin, Centre de Soins
Palliatifs de l’Hotel-Dieu, HP Paris, B Leduc Medecin, Service d’Oncologie et de Radiothérapie, Hôpital de
Brive, C Haond Medecin, Unité de Soins Palliatifs, Hôpital des Charpennes, Villeurbanne and R Schaerer
Medecin, Service d’Oncologie Médicale, CHU Grenoble
Abstract: This multicentre, randomized double-blind study was undertaken to assess
the efficacy of corticosteroids as a palliative treatment of intestinal obstruction due to
advanced and incurable cancer. Thirty-one French palliative care units agreed to
participate in the study and 12 actually recruited at least one patient. To be included,
patients had to have an advanced cancer with a surgically inoperable bowel
obstruction and to have received no specific anticancer therapy within the preceding
28 days. They had to fulfil at least three of the following criteria: vomiting at least twice
a day; colicky abdominal pain; no flatus for 12 h or more; no stool for at least 4 days,
faecal impaction being excluded; intestinal distension; air–fluid levels or absence of gas
in the colon on an abdominal radiograph.
Patients were randomized in three groups to receive either a placebo for 3 days (group
A), or methylprednisolone 240 mg daily for 3 days (group B) or methylprednisolone
40 mg daily for 3 days (group C). Symptoms were assessed daily but success or failure
of the treatment was assessed on day 4, according to the disappearance or persistence
of symptoms. Fifty-eight patients were randomized, of whom 52 were able to be
evaluated. Details of symptoms and associated treatments are described below. Of 40
patients without a nasogastric tube, symptoms were relieved in 68% of cases versus
33% among placebo-treated patients (P = 0.047). In 12 patients who had a nasogastric
tube already in place, the results are less significant (60% versus 33% with P = 0.080).
Because of the small sample size, no conclusions can be reached about the relative
efficacy of low versus high-dose treatment regimes.
Key words: palliative care; intestinal obstruction; neoplasms; methylprednisolone;
adrenal cortex hormones
Resumé: Cette étude multicentrique, randomisée, en double aveugle, a pour but
d’évaluer l’efficacité des corticostéroïdes comme traitement palliatif de l’obstruction
intestinale liée à une pathologie cancéreuse évoluée et incurable. Trente et une unités
de soins palliatifs françaises ont accepté de participer à cette étude, douze d’entre elles
ont en fait recruté au moins un patient. Pour être inclus, il fallait que les patients soient
atteints d’une obstruction intestinale inopérable et n’aient pas reçu de traitement anticancéreux spécifique dans les précédents 28 jours. Ils devaient remplir au moins trois
des critères suivants: au moins deux épisodes quotidiens de vomissements; coliques
abdominales douloureuses; pas de gaz pendant 12 heures ou plus; pas de selle depuis
Address for correspondence: Dr G Laval, Unité de Recherche
et de Soutien en Soins Palliatifs, CHU de Grenoble, BP 217,
Grenoble 38043, Cedex, France.
© Arnold 2000
0267–6591(00)PM277OA
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G Laval et al.
au moins 4 jours (fécalome exclu); distension abdominale; niveaux hydro-aériques ou
absence d’aérocolie à l’ASP.
Les patients ont été randomisés en trois groupes pour recevoir, soit un placebo
pendant 3 jours (groupe A), soit 240 mg de méthylprednisolone par jour pendant 3 jours
(groupe B), soit 40 mg de méthylprednisolone par jour pendant 3 jours (groupe C). Les
symptômes ont été notés chaque jour, mais le succès ou l’échec du traitement a été
évalué au 4ème jour: sur la disparition ou la persistance des symptômes. Cinquante
huit patients ont été randomisés, dont 52 ont pu être évalués. La description des
symptômes et des traitements associés est rapportée plus bas. Parmi les 40 patients
non porteurs de sonde naso-gastrique, les symptômes ont été relevés dans 68% des
cas versus 33% chez les patients traités par placebo (P = 0.047). Parmi les 12 patients
déjà porteurs de sonde naso-gastrique, les résultats ont été moins significatifs (60%
versus 30% avec un P = 0.080). En raison de la petite taille de l’échantillon, on ne peut
tirer aucune conclusion sur l’efficacité relative des faibles et des fortes doses.
Mots-clés: soins palliatifs; obstruction intestinale; néoplasies; méthylprednisolone;
hormones cortico-surrénaliennes
Introduction
Bowel obstruction is a frequent complication of
advanced cancer of the digestive tract1–3 or pelvic
organs.4,5 According to previous studies, this complication can occur in up to 28% of patients with
colorectal cancer and up to 42% of patients with
ovarian cancer.6 The symptoms and signs of intestinal obstruction in malignancy will depend on the
level of the obstruction, but the principal clinical
features3 include colicky abdominal pain, vomiting,
distension and increased bowel sounds with borborygmi. Constipation and the failure to pass flatus
develop insidiously in the process, and some cases
of bowel obstruction may be characterized by paradoxical (or spurious) diarrhoea. Radiological
investigations can confirm the obstruction and
determine its nature. The medical management of
patients with inoperable malignant bowel obstruction raises issues concerning the appropriateness of
various treatment options. Among available medical treatments, steroids may be useful: in certain
cases, they may resolve obstruction by reducing
inflammatory oedema around the tumour, or they
may improve intestinal motility through their antiinflammatory effects.
Even if the specific factors producing an obstruction are not completely understood,3,7 we generally know that the blockage may be either
mechanical (from intraluminal obstruction or
extraluminal compression) or functional, with
reduced motility due to impaired muscle and/or
autonomic nerve activity. Steroids have been successfully used for their anti-inflammatory effects in
the management of intracranial hypertension
caused by brain tumours,8,9 in ureteric obstruction
due to malignancy10,11 and in spinal cord compression.9,12–14 In these different therapeutic applications, drug doses have varied widely (20–1000 mg of
methylprednisolone or equivalent).
Steroids have been used in the treatment of inoperable bowel obstruction in oncology and palliative
care units,7,15–21 but without controlled studies
proving the efficacy or providing evidence of optimal dosage and routes of administration, this practice must be considered ad hoc and anecdotal. The
seminar on nausea and vomiting in advanced cancers, held at the Fifth Congress of the European
Association for Palliative Care in London in September, 199722 did not offer any new recommendations. Recent double-blind controlled clinical trials
using dexamethasone to relieve bowel obstruction
in malignancy23 have shown a beneficial effect of
steroids, but only in patients who had received
chemotherapy within 28 days of the study. Success
could also be explained by associated factors such
as chemotherapy or disease stage, but the small
number of patients in each trial (22 and 13) made
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The use of steroids in the management of inoperable intestinal obstruction 5
a statistical conclusion impossible. In addition to
our current study, a meta-analysis is planned using
these results.
We conducted a randomized trial on the use of
methylprednisolone in the treatment of nonoperable malignant bowel obstruction. The first objective
was to demonstrate the efficacy of methylprednisolone on the relief of obstruction and the
restoration of bowel function; the second was to
determine the relationship between the dose and
the desired effect.
Methods
This was a prospective study concerning patients
with symptomatic and nonoperable malignant
bowel obstruction. Initially, 31 palliative care units
in France were chosen for this study, from January
1995 to June 1997, but only 12 recruited at least one
patient. The following conditions defined the scope
of the study:
1) To be included in the study, patients had to have
advanced cancer with surgically inoperable
intestinal obstruction, to have received no specific
anticancer therapy within 28 days of study, and to
meet at least three of the following criteria:
• vomiting at least twice a day;
• colicky abdominal pain;
• no flatus for 12 h or more;
• no stool for at least 4 days (excluding cases of
faecal impaction);
• intestinal distension;
• air–fluid levels or the absence of large bowel
gas on the abdominal X-ray.
2) Patients were excluded from the study for the following reasons:
• aged less than 18 years of age;
• operable bowel obstruction;
• treatment with a steroid within the previous
10 days;
• relapse of intestinal obstruction after a previous inclusion in the study;
• an episode of bowel obstruction which could be
explained by nonmalignant causes, such as
hypokalaemia, drug side-effects, or faecal
impaction;
• signs of bowel perforation or septicaemia;
• patients incapable of expressing their own will.
3) Patients were removed from the study if:
• a nasogastric tube was placed or removed during the study;
• there was a major protocol violation;
• the patient died before day 4.
All patients were assessed with a complete physical examination, a surgical evaluation, a complete
blood cell and platelet count (CBC), and blood
chemistry. An abdominal X-ray was optional but
recommended, unless patients were too frail to be
moved.
The block method was used for the randomization of patients in each centre. This process
randomized patients into one of the following three
treatment categories: placebo, moderate dose of
methylprednisolone, or high dose of methylprednisolone.
Patients were stratified at randomization according to the presence or absence of a nasogastric tube
(NGT), because of an acknowledged role of an
NGT on the relief of symptoms.
Methylprednisolone (SOLUMEDROL from
laboratories Pharmacia, St Quentin-Yvelines,
France) was chosen because it is one of the most
widely used steroids in France. The doses used were
none (placebo group), 40 mg (moderate dose
group), and 240 mg (high dose group). The drug
was administered intravenously daily over 1 h.
Treatment lasted for 3 days. Previously prescribed
medications were continued and new drugs acting
on symptoms could be introduced, with the exception of a somatostatin analogue such as octreotide.
If a NGT was already in place at the inclusion of the
patient, it had to remain in place during the 3 days.
If a NGT had to be inserted during the 3 days, the
patient was removed from the study.
Patients were examined every day before receiving the daily injection.
On day 4, patients were examined again at the
same time, and success in resolving the bowel
obstruction was evaluated. Treatment success was
characterized by elimination of symptoms: if the
symptoms improved before the fourth day, the study
continued for the final evaluation on day 4. If the
symptoms improved temporarily and then worsened
before the fourth day, the final evaluation was completed on the fourth day.
Side-effects of methylprednisolone were noted
for each patient.
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G Laval et al.
The Pearson test (chi square) was used. A P-value
of less than 0.05 was considered as statistically
significant.
Results
Characteristics of the palliative care units and
the patients
Out of the 31 palliative care units, 12 had qualifying
patients included in the study. Of these, eight were
inpatient palliative care units and four were palliative support teams. Five units had physicians who
worked both in the cancer and palliative care units.
A total of 58 patients were included. Six left the
study: three because of death, one because a NGT
was inserted after the first day, one because the
medication was given improperly, and one because
the patient had previously been a participant. The
remaining 52 patients were analysed.
There were 19 males and 33 females, with a median age of 69.4 years. Thirty patients (57%) had a
primary cancer of the digestive tract, 16 (31%) had
a gynaecological cancer, five (10%) a urological
cancer and one (2%) a lung cancer.
Twenty-nine patients (56%) had a colonic
obstruction, eight (15%) had small bowel obstruction, two (4%) an upper duodenal obstruction and 13
(25%) had both small and large bowel obstruction.
The analysis of the clinical symptoms before the
study (Figure 1) showed that most patients passed
no stool (85%) or flatus (77%). Patients also presented with abdominal distention (83%), intestinal
colic (62%) and vomiting (62%). Abdominal X-rays
were taken in 41 of the 52 patients (79%) and
showed air–fluid levels (80%), bowel distention
(56%) and a lack of colon gas (12%). Among the
11 patients without an abdominal X-ray, five
received a placebo and six a steroid.
An analysis of associated treatments (some of
which were used in combination) was conducted
(some data were missing for four patients, see
Figure 2) and showed a moderate usage of antiemetics (25 patients, 52%), consisting of: haloperidol (18, 72%), metoclopramide (10, 40%),
hyoscine hyobromide (scopolamine) (2, 8%),
hyoscine butylbromide (butyl-hyoscinebromure)
(5, 20%), and chlorpromazine (1, 4%). Serotonin
receptor antagonists (5HT3) were not used. Antispasmodic and anti-secretory drugs (somatostatin
analogues excluded) were used in 33 (69%) cases
including: tiemonium (16, 49%), trimebutine (5,
15%), hyoscine butylbromide (5, 15%), phloroglucinol (5, 15%) and scopolamine (2, 6%). The number of patients receiving hyoscine butylbromide
(2:3) or scopolamine (1:1) was well balanced
between the placebo group and the corticosteroid
group.
Vomiting
62%
Abdominal colic
62%
Patients with
symptoms
Total = 52
No flatus
77%
85%
No stool
83%
Intestinal distension
Abdominal X-ray
80%
Air-fluid levels
Patients with
abdominal X-ray
Total = 41
56%
Bowel distension
Lack of colon gas
12%
0
10
20
30
40
Number of patients
Figure 1
Symptoms before inclusion
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50
60
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The use of steroids in the management of inoperable intestinal obstruction 7
23%
Nasogastric tube
Total = 52
(* total 48, since
missing date)
52%
Antiemetics (*)
19%
Laxatives (*)
10%
Enema
Antispasmodics (*)
69%
60%
Analgesics (*)
87%
Parenteral fluid adm.
100%
Other treatments (*)
0
20
30
Number of patients
40
50
60
Associated treatments
Analgesics were used in 29 (60%) of 48 patients:
morphine was used in 22 (77%) and paracetamol in
seven (25%) cases. Parenteral fluids were administered in 45 (87%) of the total 52 patients. All patients
continued to receive other medications consistent
with their treatment regimes, such as anti-hypertensive drugs, insulin, heparin, and tranquillizers.
The median length of survival after the inclusion
in the study was 41 days (Figure 3). Ten patients
lived less than 14 days, and only one patient lived
for 300 days.
No side-effects were attributed to steroid use.
Results on bowel obstruction
Among the 52 patients, 15 received a placebo, 19
received the moderate dose of methylprednisolone
(40 mg/daily) and 18 received the high dose
(240 mg/daily). Twelve had a NGT at the beginning
of the study.
The analysis of the group of 52 patients demonstrates that symptoms of bowel obstruction were
relieved in more of those patients taking steroids
than in those taking the placebo, although the difference did not reach statistical significance
(P = 0.08, Table 1).
The results become statistically significant
(P = 0.047, Table 2) only when those patients without a NGT were studied as a group. Only four
(33%) of the patients without a tube and receiving
a placebo had resolution, as compared with 19
(68%) of those patients without a tube who were
given steroids. In this study, and for these patients,
symptoms of bowel obstruction were relieved twice
as often in the medicated group, when compared to
the control group.
The relation between dosage and efficacy could
not be determined because of the small numbers in
the study.
Discussion
In this double-blind, randomized trial comparing
steroid with placebo in inoperable bowel obstruc10
Number of occurrences
Figure 2
10
8
19% 19%
16%
6
4
13.5%
11% 11%
8%
2
2.5%
0
7
14
28
60
90
120 180 300
Days
Figure 3
Length of life after the inclusion
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G Laval et al.
Table 1 Results for 52 patients (including 12 patients with a
nasogastric tube)
Table 2 Results for 40 patients (patients without a nasogastric tube)
Symptoms
Total
Symptoms
Controlled
Uncontrolled
15
Placebo
37
Steroids
52
Total
4
33.5%
19
68%
23
58%
8
66.5%
9
32%
17
43%
Placebo
Steroids
Total
Controlled
5
33.5%
22
59%
27
Uncontrolled
10
66.5%
15
41%
25
P = 0.080.
Total
12
28
40
100
P = 0.047.
tion, the relief of symptoms that could mean the
restoration of intestinal transit through the use of
steroids represents an interesting therapeutic
approach, but the small size of the study group (40
patients without a NGT) limits the conclusions that
can be drawn. Our accrual of new patients was disappointingly low, due to the fact that, at the present
time in France, steroids are very commonly prescribed in inoperable bowel obstruction due to
malignancy.
The choice of inclusion criteria in this trial were
based on clinical literature3,24 and French clinical
practice. The surgeon in our group insisted that a
lack of flatus and faecal material were significant
symptoms of complete bowel obstruction in
patients with advanced cancer. Their resolution was
taken to mean the beginning of the restoration of
intestinal transit.
The distinction between complete or partial
(subacute) obstruction is sometimes difficult to
determine in clinical practice. The fact that 11
(21%) patients (five with placebo and six with
steroids) had no abdominal radiography, and the
absence of other radiological investigations and
laparotomy also made the diagnosis of a complete
bowel obstruction difficult.
The limited patient number in this study does
not support any conclusions relating the treatment
effectiveness to the size of the tumour responsible
for the bowel obstruction, and the study size
also prevents conclusions concerning the most
effective steroid dose. Furthermore, in an attempt
to simplify this study design, no attempt was made
to assess the duration of benefit from the use of
steroids.
The present study involved only a 3-day treatment course, in spite of the fact that steroids need
a longer duration of use for increased effectiveness.25 This was decided for ethical considerations
related to the placebo-treated group.
The distribution of observed symptoms differs significantly from that observed by Baines.7 In her
patient population, 100% had vomiting, 76% had
abdominal colic, 13% had constipation and 34%
had diarrhoea. As she has noted, the different clinical presentations may depend on the level of the
intestinal obstruction, which is associated with
specific tumour types and stage of the illness. In our
study, a majority of the patients had a lower colon
obstruction (based on clinical and radiographic
criteria). This explains the moderate frequency of
vomiting and the high frequency of no faecal
material.
The therapeutic regimes in this study were in
common use. We did not use serotonin antagonists
in our study because they were not commonly used
at the time. The randomization between placebo
and corticosteroids regimens was aimed to balance
the possible effects of other drugs which were
allowed for ethical reasons.
It should be noted that 77% of our patients
did not have a nasogastric tube, confirming that
‘drip and suck’ is not always necessary to control
the nausea and vomiting associated with a bowel
obstruction.
The fact that the median length of survival was 41
days reminds us that this study concerns severely ill
patients who are near the end of their lives. In this
group, treatment with steroids is primarily a palliative effort directed at providing comfort to terminal
cases, and the absence of side-effects indicates that
steroids are an appropriate therapy for short-term
use. According to Twycross,22 steroids are considered
the second-line treatment for nausea after failure of
the usual antinausea and anti-emetic drugs, in part
because they are much less expensive than alternatives that are sometimes used, such as assomatostatin analogues26–28 and serotonin antagonists.29
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The use of steroids in the management of inoperable intestinal obstruction 9
Conclusion
In spite of the small study size (caused by the exclusion of patients already receiving steroids) and the
short study duration, our results suggest that
steroid use can improve the symptoms of nonoperable bowel obstruction in some terminally ill cancer
patients. Based on the facts that steroids are relatively inexpensive and are well tolerated, this study
supports their use in this setting. Additional work
may refine this general recommendation depending
on cancer type and stage, and also provide additional information about the optimal dose and duration of treatment.
Acknowledgements
We thank Dr N Steiner of Geneva for her excellent
advice and consultation for the preparation of this
study, the Registre du Cancer de l’Isère for the
methodological and statistical assistance and the
Societé Francaise d’Accompagnement et de Soutien
en Soins Pallatifs, which promoted the study and
provided financial assistance. We also thank Dr C
Hatchette of Fort Collins, CO, USA for his kind
support during the finalization of this paper and
help for linguistic correctness before submission.
List of palliative care units including at
least one patient
1) Région Parisienne et Nord-Ouest: Maison
Médicale Jeanne Garnier, Paris, Dr MS
Richard; Maison Médicale Notre Dame du Lac,
Ruel-Malmaison, Dr M Evrard, Dr F Vanhille.
2) Région Centre et Nord-Est: La Mirandière,
Quétigny, Dr J Girardier, Dr Beal; Unité de
Soins Palliatifs du CHU de Clermont-Ferrand,
Dr Hermet, Dr Hager; Service de Radiothérapie, Oncologie et Soins Palliatifs du Centre
Hospitalier de Brive, Dr B Leduc; Unité de Soins
Palliatifs des Centres Hospitaliers de Vierzon
et Bourge, Dr Essayan, Dr Fondras; Maison
Médicale Jean XXIII, Frelinghien, Dr C De
Beir; Unité de Soins Palliatifs de l’Institut Jean
Godinot, Rouen, Dr O Dubreucq; Unité de Soins
Palliatifs du Centre Hospitalier de Saint Dizier,
Dr C Devaux.
3) Région Rhone-Alpes, Sud-Est et Sud-Ouest:
Unité de Soins Palliatifs du CHU de Grenoble,
Dr G Laval, Dr P Mussault, Dr C Boillot ; Unité
de Soins Palliatifs de l’Hôpital des Charpennes,
Villeurbanne, Dr C Haond, Dr G Bilocq; Centre
Anticancéreux Léon Bérard, Lyon, Dr Rebattu.
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