Managing malignant bowel
obstruction

Professor David Currow
ImPACCT (Improving Palliative, Aged andChronic Care through Clinical Trials andTranslation)
Faculty of Health,
University of Technology Sydney
New South Wales, Australia

Managing malignant bowel
obstruction

1. Clinical trials in palliative care

2. Surgical approaches to malignant bowel
obstruction
3. Symptom control for inoperable
malignant bowel obstruction

Managing malignant bowel
obstruction

1. Clinical trials in palliative care

2. Surgical approaches to malignant bowel
obstruction
3. Symptom control for inoperable
malignant bowel obstructionImproving the evidence base forclinical practice in palliative care

Our clinical work demands that
we continue to evaluate thenet effect of ourinterventions on the people
that we serve in the mostrigorous ways available.
This is the frailest clinicalpopulation and we must
balance harms and benefitsNon-randomised versus randomised
controlled clinical trial exploring thesame question

Differences may range from a
90% underestimate of effectto a 150% overestimate
mostly with wider
confidence intervals .
Kunz R, Oxman AD. The unpredictability paradox:
review of empirical comparisons of randomised andnon-randomised clinical trials. BMJ. 1998 Oct
31;317(7167):1185-90.

Improving the evidence base forclinical practice in palliative care

So today’s fundamental
questions are:
1. What is the natural history of
inoperable bowel
obstruction due to cancer or
its treatments (malignant
bowel obstruction)?
2. Do any of our interventions
cause harms?

Improving the evidence base forclinical practice in palliative care

Given that there is no subjective
component to the assessment ofmalignant bowel obstruction for
vomiting or naso-gastric tube
secretion volumes, there is no‘placebo effect’. The placebo armof any such study defines thenatural history of the condition.

Bowel obstruction
 Operable bowel obstruction – single point

or adhesions, volvulus
 Inoperable bowel obstruction– multi-level disease– people who could not tolerate the catabolic
insult of surgery even if minimally invasive– Both– Non-surgical options are limited– No registered standard pharmacologicaltherapyBowel obstruction
 Identifiable groups at higher risk
 People with– documented intra-peritoneal disease– previous bowel obstruction

Management of malignant bowel obstruction

Epidemiology of bowel obstruction- Incidence and prevalence increase with moreadvanced disease- Rates vary widely with differing diagnoses.
Overall estimates are that 3%-15% of people
with advanced cancer will have a bowel
obstruction at some time in their clinical care.
- Median prognosis 1-9 months

Management of malignant bowel obstruction

Epidemiology of bowel obstruction
surgery non-surgical care
Mean (days)
30 day mortality
Return to oral intake
Re-obstruction rate
Time to re-obstruct
Length of stay

(n=324)(n=199)

331
26.7%
80.1%
17.9%
36
8.4

174
36.6%
80.3%
35.2%
223
15.6

Management of malignant bowel obstruction

Prognosis with cancer-related bowel obstruction
Predictors of 30 day mortality (n=523)
Clinically:
carcinomatosis
ascites
complete small bowel obstruction
Laboratory values:
hypoalbuminaemia
Henry JC et al.
Surgery 2012
leucocytosis

Management of malignant bowel obstruction

Prognosis with cancer-related bowel obstruction
Predictors of 30 day mortality (n=523: 30% ofpresentations have ≥3/5 factors at presentation)
ScoresHenry JC et al.
Surgery 2012

0 - 9.1% dead by 30 days
1 - 14.9%
2 - 21.9%
3 - 38.8%
4 - 42.9%
5 - 69.2%

Management of malignant bowel obstruction

Predictors of return to oral intake by discharge
Radiographic evidence of large bowel obstruction(OR 4.97; 95%CI 1.3, 21.9)

Henry JC et al.
Surgery 2012

Management of malignant bowel obstruction

Number of levels of obstruction
single multiple
good surgery medical management
Functional
Statuspoor

minimally medical management

invasive
surgery /stenting

Management of malignant bowel obstruction

Number of levels of obstruction
single multiple
good surgery medical management
Functional
Statuspoor

minimally medical management

invasive
surgery /stenting

Management of malignant bowel obstruction

Number of levels of obstruction
single multiple
good surgery medical management
Functional
Statuspoor

minimally medical management

invasive
surgery /stenting

Management of malignant bowel obstruction

Number of levels of obstruction
single multiple
good surgery medical management
Functional
Statuspoor

minimally medical management

invasive
surgery /stenting

Managing malignant bowel
obstruction

1. Clinical trials in palliative care

2. Surgical approaches to malignant bowel
obstruction
3. Symptom control for inoperable
malignant bowel obstruction

Management of malignant bowel obstruction

Surgery – advanced gynaecological andgastroenterological cancers
Systematic review
poor data on key issues:- patient characteristics
especially for identifying anygroup more likely to respond- outcome measures (including
Feuer DDJ et al. CDSM
toxicities)
2000, 2009
- duration of benefit

Surgical management of malignant bowel
obstruction
 There are marked variations in clinical practiceconcerning surgery in these patients between different
countries, gynaecological oncology units and generalclinical teams, as well as referral patterns fromoncologists under whom these patients are often
admitted.
Feuer
DDJ et
al.
CDSM
2000,
2009,
2016

 To assess the efficacy of surgery for intestinal

obstruction due to advanced gynaecological andgastrointestinal cancer.
.

Surgical management of malignant bowel
obstruction
 SEARCH METHODS:
 Up to June 2015:
 SELECTION CRITERIA:

 Prospective and retrospective studies
 Advanced gynaecological and gastrointestinal cancers
Feuer
DDJ et
al.
CDSM
2000,
2009,
2016

 Published trials reporting on the effects of surgery for

resolving symptoms in malignant bowel obstruction in
adultsSurgical management of malignant bowel
obstruction

RESULTS: 43 studies examining 4265 participants (up from 938

patients from 25 studies in 2000).
 No firm conclusions can be drawn from the many
Feuer
DDJ et
al.
CDSM
2000,
2009,
2016

retrospective case series so the role of surgery inmalignant bowel obstruction remains controversial.

Surgical management of malignant bowel
obstruction

Feuer
DDJ et
al.
CDSM
2000,
2009,
2016

RESULTS: Clinical resolution varies from 26.7% to over 68%,
though it is often unclear how this is defined.
 Success with ability to feed 30% - 100%.
 Rates of re-obstruction 0% - 63% although timeframes
were often not cited Postoperative morbidity and mortality varied widely There were no data available for quality of life.
 Most included studies were at high risk of bias for mostdomains.

Surgical management of malignant bowel
obstruction

RESULTS: In order to compare outcomes in malignant bowel
obstruction, there needs to be a greater degree ofstandardisation of management.
 Since the last version of this review none of the newly
Feuer
DDJ et
al.
CDSM
2000,
2009,
2016

included studies have provided additional information tochange the conclusions.

Management of malignant bowel obstruction

Surgery – advanced gynaecological cancers
Surgical versus medical management
Systematic review
Only one study, and woman with poor
function were excluded from surgery, andthose with surgery survived longer (although
3/22 died in peri-operative period). No qualityof life data were collected.
Kucukmetin A et al.
CDSM 2010

Management of malignant bowel obstruction

Surgery – advanced gynaecological cancers
Surgical versus medical management
Retrospective case note series- 53 woman. No randomisation. Poorer
function in woman who did not get surgery.
- 20 had surgery; one perioperative death; 11
colostomies and 7 ileostomies.
- Median survival 146 days in surgical group
Goto T et al. Oncol compared with 69 days in the women who had
Letters 2012
medical management.

Management of malignant bowel obstruction

Single level, poor function- new treatments in the last 25
years:- minimally invasive surgery- stenting- somatostatin analogues

Management of malignant bowel obstruction

Stenting versus minimally invasive surgery
 Surgery remains the dominant treatment for
malignant incurable large-bowel obstruction,with emerging data on self-expanding metallic
stents.
Young CJet al
Dis Colon  The aim of this study was to compare quality
Rectumof life and survival when treated with a stent or2015;58(9):838-49
surgical decompression.

Management of malignant bowel obstruction

Stenting versus minimally invasive surgery
 P - Patients with malignant incurable largebowel obstruction were randomly assigned tosurgical decompression or stent insertion.
Young CJ  O - EuroQOL EQ-5D quality of life.
et al
Dis Colon  Secondary end points: overall survival; 30-day
Rectummortality; stoma rates; postoperative recovery;
2015;58(9):838-49
complications; and readmissions.

Management of malignant bowel obstruction

Stenting versus minimally invasive surgery
 Fifty-two patients
 Stent insertion was successful in 19 of 26(73%) patients. The remaining 7 patients
Young CJ
required a stoma
et al
Dis Colon  24 of 26 (92%) surgery group required a
Rectumstoma (p < 0.001).
2015;58(9):838-49

Management of malignant bowel obstruction

Stenting versus minimally invasive surgery
 No stent-related perforations or deaths.
 Surgery group had significantly reduced
quality of life compared with the stent group
Young CJ
from baseline to 1 and 2 weeks (p = 0.001 andet al
p = 0.012), and from baseline to 12 months (pDis Colon
Rectum
= 0.01)
2015;58(9):838-49
 Both groups reported reduced quality of life.

Management of malignant bowel obstruction

Stenting versus minimally invasive surgery
 30-day mortality: stent 8%; surgery 15% (p = 0.668)
 Median survival: 5.2 and 5.5 months (p = 0.613)

 Stent group: significantly reduced:
Young CJet al
Dis Colon
Rectum2015;58(9):838-49– procedure time (p = 0.014);– post-procedure stay (p = 0.027);– days nil by mouth (p = 0.002); and– days before solids (p = 0.022)

Management of malignant bowel obstruction

Stenting versus minimally invasive surgery
CONCLUSIONS: Stent use in patients with incurable large-bowel
obstruction has a number of advantages:
Young CJet al
Dis Colon
Rectum2015;58(9):838-49– faster return to diet;– decreased stoma rates;– reduced post-procedure stay; and– some quality-of-life benefits

Managing malignant bowel
obstruction

1. Clinical trials in palliative care

2. Surgical approaches to malignant bowel
obstruction
3. Symptom control for inoperable
malignant bowel obstruction

Management of malignant bowel obstruction

Single level, good function- Exclude non-cancer related causes:
adhesions, volvulus- Is cytoreductive surgery and local or systemic
therapy indicated?

Management of malignant bowel obstruction

Multi-level obstruction, good function- A poor prognostic feature, even withrelatively good function- Are there indications for a radical
approach to managing this person’s
disease?

Management of malignant bowel obstruction- Corticosteroids for resolving malignant
bowel obstruction (n=89 patients in RCTs)- Dexamthasone 6 - 16mg per twenty fourhours
- Trend that is not statistically significant
towards resolution of bowel obstruction(NNT 6 (3 to infinity))
Feuer DDJet al.
- No excess mortality at one month in those
CDSM
2000, 2008 treated with corticosteroids

Management of malignant bowel obstruction

Medications to reduce gastrointestinal tract
secretions- 7 studies in a meta-analysis- H2 antagonists are more effective than
Clark K et
proton pump inhibitors at reducing theal.
Anaesthesia volume of gastric secretions
2009;64(6):652-7Management of malignant bowel obstruction

Multi-level obstruction, poor function- no head-to-head trials of surgery
compared to medical management- controlled trials to date ofsomatostatin analogues

Management of malignant bowel obstruction

Multi-level obstruction, poor function
Considerations- hydration- decompression / suction- oral intake- medications to:- commence- continue- ceaseOctreotide / lanreotide
 Somatostatin analogues, with lanreotide

being a monthly dose
 Different effects on small bowel (decreasedtransit time) compared to large bowel(markedly increased transit time) Theoretical benefit in bowel obstruction– reducing secretions– reducing the secretion of a number ofhormones from the upper gut that may
worsen the symptoms of bowel
obstruction

Lanreotide and octreotide
 D - double-blind, randomised study for

Laval G et al.
Bull Cancer
2012;99(2):E1-9

efficacy and safety, parallel group study
 P - peritoneal carcinomatosis andsymptoms of inoperable malignant bowel
obstruction
 I - lanreotide microparticles 30mg AND
600mcg / day octreotide (n=32 of 51 planned)
 C – placebo (n=32 of 51 planned)
 Both arms methylprednisonolone days 1-6
 O – absence of nasogastric tube, vomiting
less than 2x / day, no anticholinergic use
 Intention to treat 38% versus 28%

Lanreotide
 D - double-blind, parallel group study
 P - two episodes of vomiting andMariani P et al. J
Clin Oncol
2012;30(35):433
7-43

inoperable bowel obstruction. No further
anti-neoplastic therapy
 I - lanreotide microparticles 30mg (n=43)
 C - placebo (n=37)
 O - ≥ 3 consecutive days with one or lessepisodes of vomiting per day after nasogastric tube removal at day 7 (of 10)
 Intention to treat 42% lanreotide versus 30%
placebo (p=0.24)

Octreotide in hospice /palliative careThree early randomised controlled trials:
 Volume of nasogastric tube secretions
on days 2,3 when compared tohyoscine butylbromide (n=17)
 Vomiting and nausea when comparedto hyoscine butylbromide (n=15)
 Nausea and vomiting over baseline
when compared to chlorpromazine /hyoscine butylbromide (n=68)
Ripamonti C et al. JPSM 2000; Mercadante S et al. Supp Care Canc 2000; Mystakidou K
et al. Anticanc Res 2002

Octreotide vs placebo

Currow D et al.
J Pain Symptom
Manage.
2015;49(5):814821

D - double-blind, block randomised, fixed dose,
multi-site, parallel arm studyP - vomiting and inoperable bowel obstruction(including surgical review). No further antineoplastic therapy indicated at that time

* Potential participants were able to provide
advanced consent if they had experienced aprevious bowel obstruction or were at high risk. 63
people gave advanced consent, of whom 21 went
on to a bowel obstruction and were randomised.

Octreotide vs placeboI - octreotide 600mcg / 24 hours by infusion(n=46)
 C - placebo (n=46)
Both arms: ranitidine 200mg / 24 hours;
dexamethasone 8 mg / 24 hours; 10-20mls/kg
hydration / 24 hours

Concomitant therapy – cease prokinetic agents
 Standardised breakthrough for:

Currow D et al.
J Pain Symptom
Manage.
2015;49(5):814821– Pain - morphine– Colicky pain – hyoscine butylbromide– Nausea – haloperidol

Octreotide vs placebo

Currow D et al.
J Pain Symptom
Manage.
2015;49(5):814821

O - days free of vomiting at 72 hours and nonasogastric tube

Intention to treat 76 vomiting free days
octreotide versus 81 placebo (p=0.724)

Octreotide vs placebo

Currow D et al.
J Pain Symptom
Manage.
2015;49(5):814821

Significantly greater chance of getting hyoscine
butylbromide in the octreotide arm (5.7x by day 3)

All but four participants had small bowel
involvement



Octreotide’s effect on motility– Decreased transit time from stomach to caecum– Increased time from caecum to rectum

CONSORT diagram
Provided advanced
consent n= 64
Subsequently
randomised n = 21

Assessed as eligible
n= 118
Not randomized as did not consent
n= 4
Study medication not available = 1(Randomised but not eligible = 1)

Randomised n= 112

Deleted from analysis
n= 6
Eligibility violations atbaseline

Allocated to
Octreotide n= 52

Allocated to placebon= 54

Did not receive placebo n= 4

Did not receive octreotide n= 4
Patient deterioration = 2
Clinical/patient request = 2

Received octreotide
n= 48

Received placebo n=
50

Clinical request = 1
Other treatment = 2
Died = 1

Discontinued placebo n= 8
Discontinued octreotide n= 4
Clinical deterioration = 1
Patient/clinical request = 1
Naso gastric insertion = 2

Completed Octreotiden= 44Completed placebon= 42Clinical deterioration = 3
Patient/clinical request = 1
Nasogastric insertion = 1
Died = 1
Other reason = 2

Octreotide vs placebo –magnitude and direction ofdifferences






Currow D et al.
J Pain Symptom Manage.
2015;49(5):814821

Global impression of change – daily measures – nodifference (p=0.96)
Survival – no difference (p=0.28)
Number of episodes of vomiting no difference
Number of episodes of vomiting when controlling for age,gender, body mass index and oral intake, people onoctreotide had a 50% reduction in the incidence of vomiting
Nausea – no difference (tended to decrease in both arms;
p=0.63)Pain – no difference (p=0.81)

Octreotide vs placebo Unable to differentiate clinically between

Currow D et al.
J Pain Symptom
Manage.
2015;49(5):814821

arms
 Well tolerated interventions
 Increased use of hyoscine butylbromide
unexplained
 supports again the feasibility andimportance of RCTs in testing clinicaltherapies
 Ultimately, an adequately powered,negative study Sufficient signal to consider further researchOctreotide vs placebo D – consecutive case series P – 25 patients with MBO, 2 vomiting

episodes / day for 2 consecutive days or an
NGT I – 0.3mg / day octreotide / 6 days
 O -. 11/25 responded (resolution or
improvement in nausea or vomiting) Colicky pain was one symptom that did not
improve during treatment.
Shima Y et al.
Jpn J Clin
Oncol.
2008;38(5):354359.

Octreotide vs butylbromide Octreotide compared to scopolamine

butylbromide (SB) as an anti-secretory
medication
 Inoperable malignant bowel obstruction(MBO), advanced ovarian cancer.
 Participants 3 day infusion of– Octreotide 0.3 mg/day (n=48)– Butylbromide 60 mg/day (n=49)
Peng X et al.
World J Surg
Oncol 2015
;13:50 Outcomes: Likert scales for episodes ofvomiting; nausea; dry mouth; drowsiness;and continuous and colicky pain.

Octreotide vs butylbromide Octreotide significantly reduced the amountof GI secretions at T1, T2, and T3 (P <0.05) compared with SB.
 Nasogastric tube secretions– significantly reduced in the octreotide arm at
D1, D2, and D3 compared with baseline(p<0.05)– significantly in butylbromide group only D3compared with baseline Octreotide significantly reduced the number
Peng X et al.
World J Surg
Oncol 2015
;13:50of daily episodes of vomiting and intensityof nausea compared with butylbromideOctreotide vs butylbromide
 Continuous pain values were significantly

lower with octreotide than butylbromide D2
and D3 (p<0.05)
 No significant changes in colicky pain

Peng X et al.
World J Surg
Oncol 2015
;13:50Somatostatin analogues inmalignant bowel obstruction
 Systematic review – December 2016
 Relieving vomiting in malignant bowel

obstruction with somatostatin analogues
compared to:– placebo and/or– other pharmacologic agents
 MEDLINE, EMBASE, CINAHL, and The
Obita G et al.
J PainSymptom
Manage 2016;
52(6):901-919

Cochrane Controlled Trials Register databases
were systematically searched; reference lists ofrelevant articles were hand searched.
Cochrane risk of bias tool was used.

Somatostatin analogues inmalignant bowel obstruction
 Systematic review – December 2016

Obita G et al.
J PainSymptom
Manage 2016;
52(6):901-919

RESULTS:
 Seven randomised controlled trials (RCTs) met
the inclusion criteria (six octreotide studies andone lanreotide); 220 people administered somatostatin
analogues and 207 placebo or hyoscine
butylbromide.
 A somatostatin analogue was compared with– placebo (3 studies); and– hyoscine butylbromide (4 studies).

Somatostatin analogues inmalignant bowel obstruction
 Systematic review – December 2016

Obita G et al.
J PainSymptom
Manage 2016;
52(6):901-919

RESULTS: Two adequately powered multi-centre RCTs
with a low Cochrane risk of bias reported nosignificant difference between somatostatin
analogues and placebo in their primary end
points.
 Four RCTs with a high/unclear Cochrane riskof bias reported that somatostatin analogues
were more effective than hyoscine
butylbromide in reducing vomiting.

Somatostatin analogues inmalignant bowel obstruction
 Systematic review – December 2016

CONCLUSION:
 High-level evidence from trials with low risk ofbias found no benefit of somatostatin
analogues for their primary outcome.
 There is low-level evidence of benefit withsomatostatin analogues in the symptomatic
treatment of MBO.
Obita G et al.
J PainSymptom
Manage 2016;
52(6):901-919

Somatostatin analogues inmalignant bowel obstruction
 Systematic review – December 2016

CONCLUSION:
 There is debate regarding:– the clinically relevant study end point for
symptom control in MBO; and– when it should be measured.
 The role of somatostatin analogues in thisObita G et al.
J PainSymptom
Manage 2016;
52(6):901-919

clinical situation requires further adequately
powered, well-designed trials with agreed,clinically important end points and measures

Somatostatin analogues
 Unable to differentiate clinically betweenarms Well tolerated interventions
 Increased use of hyoscine butylbromide
unexplained
 supports again the feasibility andimportance of RCTs in testing clinicaltherapies
 Ultimately, an adequately powered,negative study Sufficient signal to consider further researchConservative management ofmalignant bowel obstruction
Limited evidence to date from individual
studies or meta-analyses
No definitions of standard therapies

Further key work needs to be done, but finallyanswering the role of corticosteroids and of H2
antagonists seems crucial

Managing malignant bowel
obstruction

1. Clinical trials in palliative care

2. Surgical approaches to malignant bowel
obstruction
3. Symptom control for inoperable
malignant bowel obstruction