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Abstract
Background Guidance: the practical management of the gastrointestinal symptoms of pelvic radiation disease was published in 2014 for a multidisciplinary audience. Following this, a companion guide to managing upper gastrointestinal (GI) consequences was developed.
Aims The development and peer review of an algorithm which could be accessible to all types of clinicians working with patients experiencing upper GI symptoms following cancer treatment.
Methods Experts who manage patients with upper GI symptoms were asked to review the guide, rating each section for agreement with the recommended measures and suggesting amendments if necessary. Specific comments were discussed and incorporated as appropriate, and this process was repeated for a second round of review.
Results 21 gastroenterologists, 11 upper GI surgeons, 9 specialist dietitians, 8 clinical nurse specialists, 5 clinical oncologists, 3 medical oncologists and 4 others participated in the review. Consensus (defined prospectively as 60% or more panellists selecting ‘strongly agree’ or ‘agree’) was reached for all of the original 31 sections in the guide, with a median of 90%. 85% of panellists agreed that the guide was acceptable for publication or acceptable with minor revisions. 56 of the original 61 panellists participated in round 2. 93% agreed it was acceptable for publication after the first revision. Further minor amendments were made in response to round 2.
Conclusions Feedback from the panel of experts developed the guide with improvement of occasional algorithmic steps, a more user-friendly layout, clearer time frames for referral to other teams and addition of procedures to the appendix.
- OESOPHAGEAL CANCER
- GASTRIC CANCER
- PANCREATIC CANCER
- QUALITY OF LIFE
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Introduction
This guide is designed for all clinicians who look after people who have been treated for upper gastrointestinal (GI) cancer. It is also designed for patients who are experiencing upper GI symptoms following any cancer treatment. Some of these will be doctors, others may be senior nurses and increasingly, other allied health professionals.
Some lower GI symptoms are also included because these are common after treatment for upper GI cancers. However, for more detailed advice about managing lower GI symptoms please refer to Guidance: The practical management of the gastrointestinal symptoms of pelvic radiation disease.1
The GI consequences of chemotherapy, radiotherapy and resectional surgery are not that different. Historically, clinicians have associated specific clusters of symptoms with typical diagnoses especially in patients who have been treated for upper GI and hepatopancreatobiliary cancer. Research increasingly suggests that specific symptoms are not reliable indicators of the underlying cause, hence, this algorithmic approach.
This guide defines best practice although not every investigation modality or treatment may be available in every hospital.
Those using the guide, especially if non-medically qualified, should identify a senior gastroenterologist or other appropriately qualified and experienced professionals whom they can approach easily for advice if they are practicing in an unsupervised clinic.
Practitioners should not use this guide outside the scope of their competency and must identify from whom they will seek advice about abnormal test results which they do not fully understand before using the guide.
Specific therapies are usually not listed by name but as a ‘class’ of potential drugs as different clinicians may have local constraints or preferences as to the medications available.
Arranging all first line suggested investigations required by the symptom(s) at the first consultation reduces follow-up and allows directed treatment of all causes of symptoms at the earliest opportunity. Timely review of requested investigations is required so that further investigations can be requested if required. If worrying symptoms are elicited or potentially abnormal findings are present on clinical examination, then the order of investigations suggested in the algorithm may no longer be appropriate.
Practitioners seeing these patients are encouraged to consider providing patients with symptom questionnaires including nutritional screening questions to complete before or during the consultation as this may help improve the choice of investigations and identify when referral is required.
This guide has three parts:
An introduction, instructions how to use the algorithm, guide to blood tests and taking a history.
An algorithm detailing the individual investigations and treatment of each of the 28 GI symptoms.
Appendices with brief descriptions of the diagnosis, treatment and management techniques available.
HOW TO USE THE ALGORITHM
Up to 28 symptoms have been described in this patient group.
Each symptom may have more than one contributing cause.
Symptoms must be investigated systematically otherwise causes will be missed.
Identify the symptoms by systematic history taking.
Examine the patient appropriately.
Use the algorithm to plan investigations.
Most patients have more than one symptom and investigations need to be requested for each symptom.
Usually all investigations are requested at the same time and the patient reviewed with all the results.
When investigations should be ordered sequentially, the algorithm indicates this by stating first line, second line, etc.
Treatment options are generally offered sequentially but clinical judgement should be used.
Guide to using blood tests
Routine blood tests include: full blood count, urea and electrolytes, liver function, glucose, calcium (table 1).
Routine blood tests: responding to results
Additional blood tests are indicated depending on the presenting GI symptoms and differential diagnoses as outlined in the algorithm (table 2).
They potentially include: erythrocyte sedimentation rate, C reactive protein, red cell folate, iron studies, vitamin B12, thyroid function test, coeliac serology (tissue transglutaminase IgA), magnesium, amylase (table 2).
Addtional blood tests: responding to results
Specific tests are indicated depending on the symptoms/diagnosis as outlined in the algorithm.
They may include fat soluble vitamins, trace elements, fasting gut hormones, international normalised ratio, haematinics (table 3).
Specific blood tests: responding to the results
Taking an appropriate history
Patients cannot be helped without an accurate history being taken.
Taking a history of GI symptoms is a skill that must be learnt.
Specialist units find that symptom questionnaires completed by the patient before the consultation often help clarify which issues are really troubling the patient.
Take a broad approach: for example, after treatment for upper GI cancer, patients also frequently develop troublesome lower GI symptoms.
Taking a history needs to elicit
What was GI function like before the cancer emerged?
How have the symptoms changed over time and how severe are they?
If the patient has received multimodality treatment, how did symptoms change after each treatment component was delivered?
Are key features indicative of potentially serious underlying pathology present, for example,
Rapid progressive worsening of symptoms?
Rapid weight loss?
Has the patient noticed any masses?
Are there key features possibly indicative of reversible underlying pathology present, for example,
Sudden onset symptoms?
Nocturnal waking from the symptom?
Development of steatorrhoea?
Is there a consistent impact of a specific component of diet on their symptoms, especially:
Alcohol intake?
Are they eating/drinking too much at each sitting?
Are they eating erratically?
Fat intake?
Fibre: how much are they eating—too much/too little?
Gluten-containing foods?
Lactose-containing foods?
Other carbohydrates intake?
Is there an association between the start of specific medication or increase in its dose and their symptoms—for example, metformin, lansoprazole, β-blockers?
Ask specifically about the presence of intermittent steatorrhoea (see p. 22). After upper GI cancer, this commonly indicates the development of one or more of the following:
Small intestinal bacterial overgrowth.
Pancreatic insufficiency.
Severe bile acid malabsorption (BAM).
The GI symptoms
APPETITE: POOR/REDUCED (anorexia) (supplementary figure 1 and table 4)
Investigation and management of anorexia
Supplementary figures
BELCHING/BURPING (eructation) (Supplementary figure 2 and table 5)
Investigation and management of belching/burping
Bloating
An uncomfortable feeling that the abdomen is full or distended or visibly swells (Supplementary figure 3 and table 6).
Investigation and management of bloating
Borborygmi
Rumbling/gurgling noises in the abdomen (Supplementary figure 4 and table 7).
Investigation and management of borborygmi
CHANGE IN SENSE OF SMELL (hyposmia, anosmia or parosmia) The reduced ability, inability or distortion of sensation of odour (Supplementary figure 5 and table 8).
Investigation and management of change in smell
CHANGE IN SENSE OF TASTE (hypogeusia, ageusia or dysgeusia) The reduced ability, inability or distortion of sensation of taste (Supplementary figure 6 and table 9).
Investigation and management of change in taste
CHRONIC COUGH (tussis) lasting longer than 3 weeks (Supplementary figure 7 and table 10)
Investigation and management of chronic cough
Diarrhoea
Stool type 6–7 on the Bristol stool chart.3 Not increased frequency of type 1–5 (Supplementary figure 8 and table 11).
Inestigation and management of diarrhoea
DRY MOUTH (xerostomia) (Supplementary figure 9 and table 12)
Investigation and management of a dry mouth
Dumping
For dumping, please refer to the section ‘Postprandial dizziness/sweating/palpitations’ on page 20.
DYSPHAGIA—HIGH (oropharyngeal dysphagia).
Difficulty with swallowing/sensation of food sticking (Supplementary figure 10, tables 13 and 14).
Swallowing score
Investigation and management of high dysphagia
DYSPHAGIA—LOW (oesophageal dysphagia)
Difficulty with swallowing/sensation of food sticking (Supplementary figure 11, tables 15 and 16).
Swallowing score
Investigation and management of low dyphagia
EARLY SATIETY
Feeling full after eating a small amount of food (Supplementary figure 12 and table 17).
Investigation and management of early satiety
EPIGASTRIC PAIN CHRONIC (>2 weeks)
Pain localised to the region of the upper abdomen immediately below the ribs (Supplementary figure 13 and table 18).
Investigation and management of chronic epigastric pain
GI BLEEDING (haematemesis and/or melaena)
Vomiting blood or ‘coffee grounds’ and/or black ‘tarry’ faeces associated with upper GI bleeding (Supplementary figure 14 and table 19).
Investigation and management of upper GI bleeding
HALITOSIS
An unpleasant odour emitted from the mouth (Supplementary figure 15 and table 20).
Investigation and management of halitosis
HICCUPS (singultus) (Supplementary figure 16 and table 21)
Investigation and management of hiccups
HOARSE VOICE (dysphonia) (Supplementary figure 17 and table 22)
Investigation and management of hoarseness
HYPERSALIVATION/DROOLING (sialorrhoea) present longer than 3 weeks
Production of excessive oral secretions which are not swallowed (Supplementary figure 18 and table 23).
Investigation and management of hypersalivation
Jaundice
Yellowish pigmentation of the skin, the conjunctival membranes over the sclerae and other mucous membranes caused by high blood bilirubin levels (Supplementary figure 19 and table 24).
Investigation and management of jaundice
NAUSEA WITHOUT DYSPHAGIA
Feeling of sickness in the stomach marked by an urge to vomit.
If dysphagia is present with nausea, follow dysphagia guidance in tables 14 and 16.
Investigation and management of nausea
PAIN ON SWALLOWING (odynophagia) (Supplementary figure 21 and table 26)
POSTPRANDIAL DIZZINESS/SWEATING/PALPITATIONS/SOMNOLENCE AFTER OESOPHAGECTOMY/GASTRECTOMY/PANCREATECTOMY (Supplementary figure 22 and table 27)
Investigation and management of potential dumping
REFLUX (acid/bile)/heartburn
If dysphagia is present with reflux, follow dysphagia guidance in tables 14 & 16 instead.
In gastro-oesophageal reflux, acid refluxes from the stomach into the oesophagus. In duodenogastric reflux, bile refluxes from the duodenum into the stomach and oesophagus (Supplementary figure 23 and table 28).
Investigation and management of reflux
REGURGITATION
The expulsion of material from the mouth, pharynx or oesophagus, usually characterised by the presence of undigested food (Supplementary figure 24 and table 29).
Investigation and management of resurgitation
STEATORRHOEA
The presence of excess fat in the stool. Stools may float, be difficult to flush away and have an oily appearance. Sometimes pale (chalk/sand) in colour. Sometimes an oily film can be seen in the lavatory water after defaecation (Supplementary figure 25 and table 30).
Investigation and management of steatorrhoea
VOMITING (emesis)
If dysphagia is present, follow dysphagia guidance in tables 14 and 16 instead (Supplementary figure 26 and table 31).
Investigation and management of vomiting
WEIGHT LOSS (unintentional)
Reduction of the total body mass >5% in 3 months, due to a mean loss of fluid, body fat or lean mass (Supplementary figure 27 and table 32).
Investigation and management of weight loss
Appendices
Guidelines for dilatation
For a stricture in the oesophagus that is anastomotic, a tumour or radiation-induced in nature.11
Should be performed only by experienced endoscopists.
If tumour is present, endoscopic intervention should only occur after multidisciplinary team (MDT) discussion.
Dilate to a maximum diameter 15–20 mm.
Dilate for 20–60 s if using a balloon.
Dilatation >12 mm not required for stent insertion.
Do not exceed diameter of the stricture by >7–8 mm/session.
Risks are increased after chemotherapy/radiotherapy/if tumour is present.
How to perform a small intestinal aspirate
On intubation with a gastroscope, avoid aspirating oral or oesophageal fluid.
Flush 100 mL of sterile saline into the small intestine via the endoscope channel.
Follow this by 20 mL of air to ensure no saline remains in the endoscope channel.
Turn down the suction.
Leave the fluid to equilibrate with the intestinal contents for a few seconds. Aspirate 20 mL of fluid into a sterile trap.
Send the aspirate sample directly to microbiology.
Management of acid or bile related inflammation in the stomach
Lifestyle management advice
Avoid eating late at night.
Elevate the head of the bed.
Treat constipation. (p. 26).
Use of an alginate, for example, Gaviscon.
Management of acid related inflammation
Assess for Helicobacter pylori.
Proton pump inhibitor.
Management of bile related inflammation
Fresh orange juice.
Mucaine/oxetacaine.
Sucralfate suspension.
Altacite.
Prokinetics (p. 26).
Management of bile acid malabSorption/bile acid diarrhoea
Definition
Bile is secreted by the liver in direct response to the amount of ingested dietary fat. Bile acid malabsorption (BAM)/bile acid diarrhoea (BAD) is a defect in the enterohepatic circulation of bile acids. BAM occurs in the presence of ileal dysfunction when ability to absorb bile acids in the terminal ileum is impaired. BAD occurs when hepatic overproduction overwhelms terminal ileal absorption capacity.12
Common causes of BAM/BAD
Chemotherapy
Ileal disease/resection
Upper GI resectional surgery including cholecystectomy
Pancreatic disease
Pelvic radiotherapy
Idiopathic
Diagnosis
23-seleno-25-homotaurocholic acid (SeHCAT) scan
C4 blood test
Trial of bile acid sequestrant
Severity scores of BAM/BAD when using SeHCAT
7 day SeHCAT retention BAM/BAD status
15–20% borderline BAM/BAD
10–15% mild BAM/BAD
5–10% moderate BAM/BAD
<5% severe BAM/BAD
Treatment
Options include:
Dietary fat reduction
Antidiarrhoeal medication
Bile acid sequestrant
Options 1 and 2 may be useful in mild BAM/BAD. Generally bile acid sequestrants are required for moderate BAM/BAD. For severe BAM/BAD, most patients need a bile acid sequestrant and advice about long-term reduction in dietary fat intake.13
Drugs that may be helpful include aluminium hydroxide, budesonide, colesevelam, colestipol and colestyramine.
Patients with steatorrhoea usually require colesevelam.
If dietary intervention is required, advice to reduce dietary fat intake to 20% of total calories can be useful but requires dietetic expertise, patient education and supportive literature.
Many patients with moderate/severe BAM/BAD will be deficient in trace elements and fat soluble vitamins. These should be checked periodically and supplemented as appropriate.
Management of carbohydrate malabsorption
For example, lactose or other disaccharide intolerance.
Definition
Intolerance occurs from the inability to digest carbohydrates. Lactose, a component of milk and some other dairy products, is the intolerance most frequently recognised. It is due to lack of the enzyme lactase in the small intestine. Primary hypolactasia affects 70% of the world's population. Lactose or other disaccharide or monosaccharide (eg, fructose) malabsorption may occur de novo during cancer therapies (such as 5-fluorouracil chemotherapy or radiotherapy), due to damage to brush border enzymes and in some patients persists in the long term.14 ,15
Diagnosis of carbohydrate intolerance
Trial of exclusion of products containing that specific carbohydrate in diet for 1–2 weeks. Patient to keep a record of symptoms before and during the exclusion.
Specific carbohydrate breath test. Maybe falsely positive in the presence of small intestinal bacterial overgrowth (SIBO).
Small intestine biopsies and assessment for the specific disaccharide or monosaccharide activity.
Treatment
Long-term exclusion of products containing the carbohydrate in diet.
Dietetic assessment to ensure diet remains balanced. With lactose intolerance special attention should be paid to calcium intake. Other bone health risk factors should also be considered and vitamin and mineral supplementation started as appropriate.14
Consideration of a low fermentable oligo-di-monosaccharides and polyols diet.
Oral lactases for isolated lactose intolerance.
Management of constipation16
Dietary advice about healthy fibre and fluid intake.
Lifestyle advice about daily exercise.
Making time to have a toileting routine, correct positioning on the lavatory.
Medications advice.
Rectal evacuant (eg, glycerine suppositories). More effective if used 30 min after a meal.
Non-fermented bulk laxative±rectal evacuant.
Management of exocrine pancreatic insufficiency
Definition
Exocrine pancreatic insufficiency is the inadequate production and/or secretion of pancreatic enzymes and may occur after pelvic radiotherapy with para-aortic lymph node irradiation, cancer chemotherapy, acute pancreatitis, pancreatic cancer, upper GI or hepatobiliary surgery and in patients treated with a somatostatin analogue for a neuroendocrine tumour.
Diagnosis
Non-liquid stool sample for faecal elastase measurement (<200 μg FE1 per 1 g stool)—falsely low readings may be present in patients with small intestinal bacterial overgrowth.
Clinical response to pancreatic replacement.
Treatment
Pancreatic enzyme replacement therapy: requires equivalent of at least 200 000 international units Creon per day (other available brands include Nutrizym, Pancrease HL, Pancrex).
Starting dose 50 000–75 000 units of lipase with a meal and 25 000–50 000 units with a snack. The final dose of supplement will depend on type of food eaten and symptomatic response.
Use pancreatic enzyme replacement therapy with all meals, drinks and snacks, except black tea, black coffee or water.
Patients need written guidance on use of enzyme replacement.
Consider long-term multivitamin and trace element supplementation.
Consider dietetic advice to optimise bowel function.
Occasionally addition of proton pump inhibitor is required to reduce loss of replacement enzymes by gastric acid.
Long-term management
Ongoing treatment with pancreatic enzyme replacement medication.
Management of gastric dysmotility
May be more effective when used in combination or cyclically
Effects on stomach
Erythromycin: largely ineffective after 4–8 weeks through tachyphylaxis. Recommended dose 250 mg twice daily as a syrup 30 min before food. Or consider azithromycin 250 mg on alternate days.19
Domperidone: no tachyphylaxis for 8 weeks, may occur after longer use. Recommended dose 10 mg four times a day 30 min before food as a syrup orally or 30 mg four times a day as a rectal suppository. Small increased risk of cardiac arrhythmia. Current MHRA advice20 is that its use should be restricted to 1 week.
Metoclopramide: risk of tardive dyskinesia with use >3 months.
Naloxone by subcutaneous infusion.
Paroxetine—stimulates small intestinal motility only.
Consider gastric pacemaker.
Medicines & Healthcare Products Regulatory Agency (MHRA) has issued a number of warnings about the risks of using some of these medications for a longer period.20 Prescribers should be aware of local policies with regard to the use of these drugs.
Management of SIBO
Definition
SIBO is the presence of excessive bacteria in the small intestine. Small bowel bacterial overgrowth is a common cause for any GI symptom after chemotherapy and upper GI surgery. For any symptom resistant to conventional treatment, consider the possibility of SIBO.
Diagnosis
Glucose hydrogen methane breath testing±small intestine aspirate (p. 25) via upper GI endoscopy.
Red blood cell (RBC) folate and total serum bile acid levels may be elevated and vitamin B12 levels and faecal elastase may be low.
10–15% patients with negative tests still have SIBO.
Suggested antibiotic treatment options if no growth on culture to direct treatment
(If uncertain, discuss with gastroenterologist/microbiologist)
Seven days to 10 days treatment with:
Ciprofloxacin 500 mg twice daily.
Clarithromycin 500 mg twice daily.
Co-amoxiclav 625 mg three times a day.
Doxycycline 200 mg day 1, 100 mg days 2–7/10.
Metronidazole 400 mg three times a day.
Rifaximin 550 mg twice daily.
Vancomycin 250 mg four times a day.
Symptoms can recur any time after antibiotics are stopped because the underlying cause of bacterial overgrowth cannot always be addressed. If symptoms return, repeat treatment with antibiotics for a few days every month or continually at the lowest effective dose may be helpful in managing symptoms in the long term. Some clinicians recommend rotating antibiotics but this may not be effective if the organisms involved are not sensitive to the antibiotics used.
Treatment decisions should be individualised and consider the risks of long-term antibiotic therapy such as Clostridium difficile infection, cumulative irreversible neuropathy with metronidazole, Achilles tendon rupture with ciprofloxacin, intolerance, side effects, bacterial resistance and costs.14 ,21–24
Medications that may induce mucositis or change in sense of taste
Chemotherapy drugs that cause mucositis can cause development of mouth sores. Such drugs include:25
Alemtuzumab (Campath)
Bleomycin (Blenoxane)
Capecitabine (Xeloda)
Cetuximab (Erbitux)
Docetaxel (Taxotere)
Doxorubicin (Adriamycin)
Epirubicin (Ellence)
Fluorouracil (5-FU)
Methotrexate (Rheumatrex)
Vincristine (Oncovin)
Other medicines that have been linked to the development of mouth sores include:
Aspirin
Gold used to treat rheumatoid arthritis
Nicorandil
Penicillin
Phenytoin
Sulfonamides (used in a variety of medications)
Streptomycin
Many other medicines have been linked to taste changes:
Antibiotics
– Ampicillin
– Bleomycin
– Cefamandole (cephalosporin)
– Levofloxacin (Levaquin)
– Lincomycin (treatment for mycoplasma and plasmodium)
– Metronidazole
– Tetracyclines
Antiepileptics
– Carbamazepine
– Phenytoin
Antifungals
– Amphotericin B
Antihistamines
– Chlorpheniramine maleate
Antipsychotics
– Lithium
– Trifluoperazine (sometimes also used to treat nausea and vomiting)
Asthma medicines
– Bamifylline
Biological agents
– Erlotinib (Tarceva)
– Sunitinib (Sutent)
Bisphosphonates
– Etidronate
Blood pressure medications
– Captopril
– Diltiazem
– Enalapril
Blood thinners
– Dipyridamole
Cardiac medications
– Nicorandil
– Nitroglycerine patch
Cancer chemotherapy agents
Corticosteroids
– Dexamethasone
– Hydrocortisone
Diabetes medications
– Glipizide
Diuretics
– Amiloride
– Ethacrynic acid (loop diuretic)
Glaucoma medications
– Acetazolamide
Gout medications
– Allopurinol
– Colchicine
Immunosuppressants
– Azathioprine
Iron
– Iron sorbitex (given by injection)
Muscle relaxants
– Baclofen
Parkinson's disease medications
– Levodopa
Smoking cessation products
– Nicotine skin patch
Thyroid medicines
– Carbimazole
– Methimazole
Acknowledgments
The authors thank the following experts who participated in the Delphi process and provided detailed feedback on this algorithm. Dr Ana Wilson, Mr Paul Wilkerson, Dr Katherine White, Dr Jonathan Wadsley, Mr Timothy Underwood, Mr Sukhbir Ubhi, Dr Jeff Turner, Dr John Todd, Professor Anne Thomas, Mrs Gemma Tham, Dr Kathy Teahon, Miss Nicola Sunderland, Mr Duncan Stewart, Dr Howard Smart, Mr Richard Skipworth, Dr Hamid Sheikh, Dr Charlotte Rutter, Ms Claudia Rueb, Dr Dan Rogers, Ms Alexandra Robson, Miss Briony Robinson, Dr Asad Qureshi, Dr Sue Priestly, Miss Laura Pope, Dr Zinu Philipose, Dr Daniel Pearl, Miss Margaret O'Donnell, Professor Muntzer Mughal, Mrs Kàren Morgan, Miss Sarah Moore, Mrs Fiona Mitchell, Ms Laura McGeeney, Dr Astrid Mayer, Dr Thiriloganathan Mathialahan, Dr Mohid Khan, Dr Shanil Kadir, Mrs Elaine Jones, Professor Sauid Ishaq, Miss Christina Iezzi, Miss Orla Hynes, Mrs Fiona Huddy, Dr Richard Hubner, Dr Jacquelyn Harvey, Mr Richard Hardwick, Dr Emma Greig, Dr John Green, Mr James Gossage, Mr Mike Goodman, Dr Jason Dunn, Miss Louise Davey, Dr Benjamin Colleypriest, Ms Saira Chowdhury, Mrs Emma Chester, Dr Nicola Burch, Ms Melissa Brennan, Mr David Bowrey, Dr Erica Beaumont, Miss Cara Baker and three other reviewers who requested not to be acknowledged
References
Footnotes
Contributors All authors contributed to the study design. Algorithm development was performed by HJNA, ACM and ARD. Guarantor of the article HJNA.
Funding National Institute for Health Research and the Royal Marsden Biomedical Research Centre. Some of the work in compiling this guide was facilitated by funding received from Macmillan Cancer Support.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.