H. Jervoise N. Andreyev

Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer

Backgound The number of patients with chronic gastrointestinal (GI) symptoms after cancer therapies which have a moderate or severe impact on quality of life is similar to the number diagnosed with inflammatory bowel disease annually. However, in contrast to patients with inflammatory bowel disease, most of these patients are not referred for gastroenterological assessment. Clinicians who do see these patients are often unaware of the benefits of targeted investigation (which differ from those required to exclude recurrent cancer), the range of available treatments and how the pathological processes underlying side effects of cancer treatment differ from those in benign GI disorders. This paper aims to help clinicians become aware of the problem and suggests ways in which the panoply of syndromes can be managed. Methods A multidisciplinary literature review was performed to develop guidance to facilitate clinical management of GI side effects of cancer treatments. Results Different pathological processes within the GI tract may produce identical symptoms. Optimal management requires appropriate investigations and coordinated multidisciplinary working. Lactose intolerance, small bowel bacterial overgrowth and bile acid malabsorption frequently develop during or after chemotherapy. Toxin-negative Clostridium difficile and cytomegalovirus infection may be fulminant in immunosuppressed patients and require rapid diagnosis and treatment. Hepatic side effects include reactivation of viral hepatitis, sinusoidal obstruction syndrome, steatosis and steatohepatitis. Anticancer biological agents have multiple interactions with conventional drugs. Colonoscopy is contraindicated in neutropenic enterocolitis but endoscopy may be life-saving in other patients with GI bleeding. After cancer treatment, simple questions can identify patients who need referral for specialist management of GI symptoms. Other troublesome pelvic problems (eg, urinary, sexual, nutritional) are frequent and may also require specialist input. The largest group of patients affected by chronic GI symptoms are those who have been treated with pelvic radiotherapy. Their complex symptoms, often caused by more than one diagnosis, need systematic investigation by gastroenterologists when empirical treatments fail. All endoscopic and surgical interventions after radiotherapy are potentially hazardous as radiotherapy may induce significant local ischaemia. The best current evidence for effective treatment of radiation-induced GI bleeding is with sucralfate enemas and hyperbaric oxygen therapy. Conclusions All cancer units must develop simple methods to identify the many patients who need help and establish routine referral pathways to specialist gastroenterologists where patients can receive safe and effective treatment. Early contact with oncologists and/or specialist surgeons with input from the patients family and friends often helps the gastroenterologist to refine management strategies. Increased training in the late effects of cancer treatment is required.

Radiation enteropathy-pathogenesis, treatment and prevention

Changes in cancer incidence and mortality have been modest during the past several decades, but the number of cancer survivors has almost tripled during the same period. With an increasing cohort of cancer survivors, efforts to prevent, diagnose and manage adverse effects of cancer therapy, in general, and those of radiation therapy specifically, have intensified. Many cancer survivors have undergone radiation therapy of tumours in the pelvis or abdomen, thus rendering the bowel at risk of injury. In fact, the current prevalence of patients who have long-term radiation-induced intestinal adverse effects exceeds that of IBD. Considerable progress towards reducing toxicity of radiation therapy has been made by the introduction of so-called dose-sculpting treatment techniques, which enable precise delivery of the radiation beam. Moreover, new insights into the underlying pathophysiology have resulted in an improved understanding of mechanisms of radiation-induced bowel toxicity and in development of new diagnostic strategies and management opportunities. This Review discusses the pathogenesis of early and delayed radiation-induced bowel toxicity, presents current management options and outlines priorities for future research. By adding insight into molecular and cellular mechanisms of related bowel disorders, gastroenterologists can substantially strengthen these efforts.

Fiber in the treatment and maintenance of inflammatory bowel disease: a systematic review of randomized controlled trials.

Background:Dietary fiber may favorably influence fermentation, gastrointestinal inflammation, and disease progression in Crohns disease, ulcerative colitis (UC), and pouchitis and offer an attractive therapeutic addition to pharmacological treatment. This systematic review appraised data from randomized controlled trials of fiber in the management of inflammatory bowel disease. Methods:The review followed Cochrane and PRISMA recommendations. Seven electronic databases were searched along with hand searching and contacting experts. Inclusion criteria were randomized controlled trials of the effects of fiber on clinical endpoints (primarily disease activity for treatment or maintenance) or physiological outcomes in patients with inflammatory bowel disease. Results:In total, 23 randomized controlled trials fulfilled the inclusion criteria (UC, 10; Crohns disease, 12; and pouchitis, 1) recruiting 1296 patients. In UC, 3/10 studies reported fiber supplementation to benefit disease outcomes. In Crohns disease, 0/12 studies and in pouchitis 1/1 study reported a benefit on disease activity. Despite this, a number of studies reported favorable intragroup effects on physiological outcomes including fecal butyrate, fecal calprotectin, inflammatory cytokines, microbiota, and gastrointestinal symptom indices. Meta-analysis was not possible. Conclusions:There is limited weak evidence for the efficacy of fiber in improving disease outcomes in UC and pouchitis. The potential antiinflammatory role of fiber is intriguing and merits further investigation in adequately powered clinical trials. Excluding overt gastrointestinal obstruction, there was no evidence that fiber intake should be restricted in patients with inflammatory bowel disease.

“Pelvic radiation disease”: New understanding and new solutions for a new disease in the era of cancer survivorship

Abstract Background. Cancer therapies increasingly achieve cure, but result in chronic moderate or severe gastrointestinal side effects in millions of patients worldwide. Paradoxically, modern therapies threaten to increase the burden of chronic gastrointestinal toxicity, not reduce it. Aim. To define pelvic radiation disease. Methods. A reinterpretation of published data. Results. The lack of interest in patients with pelvic radiation disease is startling. Symptoms after radiotherapy are only a manifestation of new onset gastrointestinal physiological deficits induced by the radiotherapy. With proper diagnosis and treatment of these deficit(s), the symptoms are curable. Science suggests that much radiotherapy-induced gastrointestinal morbidity is preventable. Once the true nature of radiation injury is understood, straightforward solutions emerge and inaccurate dogmas can be discarded. Imprecise language is a fundamental barrier to progress in complex disorders. Conclusions. Radiation-induced gastrointestinal toxicity is bedeviled by inappropriate terminology, causing confusion, and myth which legitimizes inappropriate clinical behavior. We must address honestly the uncomfortable reality that doctors, sometimes do harm. Not to do so in an era where survivorship is a reality, will deny millions often with severe symptoms from “pelvic radiation disease”, the care which will help them.

Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective chart review and patient questionnaire.

BACKGROUND Commercially available bile-acid sequestrants are not well tolerated by >80% of patients. OBJECTIVE The aim of the present study was to assess the effectiveness and tolerability of colesevelam hydrochloride in patients who developed bile-acid malabsorption after cancer therapy. METHODS The present study comprised 2 parts: a retrospective chart review of the electronic patient records and a patient questionnaire assessing outcome measures. All patients included in this study had a diagnosis of cancer and were being followed up in a cancer clinic at The Royal Marsden Hospital. In addition, all had symptoms of bile-acid malabsorption for >3 months and had been prescribed colesevelam in the gastroenterology clinic at the hospital. The electronic records of patients who were prescribed colesevelam between 2004 and 2007 were obtained from the hospital pharmacy. Those patients who were prescribed colesevelam and did not take any of the prescribed medication or did not return for a follow-up clinical review were excluded. To help further assess outcomes, a questionnaire was mailed to patients who were still residing in the United Kingdom, were not terminally ill, and were not lost to follow-up. The questionnaire comprised questions that assessed medication history (ie, whether patients were still taking colesevelam or not [and the reason for not taking colesevelam]), dosage, effectiveness for symptom relief, and adverse events. RESULTS In total, 45 patients (37 women and 8 men; median age, 58 years [range, 32-89 years]) who received treatment with colesevelam between 2004 and 2007 were included. Of these, 36 were sent a questionnaire and 30 responded. Identifiable causes of bile acid malabsorption in this sample population were pelvic radiotherapy (n = 29), small-bowel resection (12), upper gastrointestinal surgery (2), high-dose chemotherapy (1), and new-onset Crohns disease (1). Of these patients, 67% (30/45) had not previously responded to cholestyramine treatment, but following treatment with colesevelam, this group had a recorded improvement in: diarrhea, 83% (25/30); urgency of defecation, 74% (20/27); frequency of defecation, 72% (21/29); steatorrhea, 71% (12/17); abdominal pain, 68% (15/22); and fecal incontinence, 62% (13/21). Based on the medical chart review and the patient questionnaire, after colesevelam treatment, the following proportions of all 45 patients studied experienced improvement in symptoms: loose stool (diarrhea), 88% (medical chart) and 80% (questionnaire); frequency of defecation, 77% and 83%, respectively; steatorrhea, 76% and 80%; urgency of defecation, 76% and 80%; abdominal pain, 74% and 58%; and fecal incontinence, 69% and 74%. During the study period, 15 patients discontinued colesevelam: ineffectiveness, 5; adverse events, 5 (because >or=1 of the following: bloating, constipation, heartburn, abdominal pain, flatulence, or perianal soreness); and other reasons, 7 (too many tablets or tablets difficult to swallow [3]; symptoms resolved [2]; colesevelam replaced with another medication [1]; and lost to follow-up [1]). Sixty-seven percent (30/45) of patients continued using colesevelam for up to 4 years. CONCLUSION In view of the data found in this retrospective chart review and patient questionnaire, prospective, double-blind, placebo-controlled trials of colesevelam for bile acid malabsorption are warranted.

Evaluating the efficacy of statins and ACE-inhibitors in reducing gastrointestinal toxicity in patients receiving radiotherapy for pelvic malignancies

INTRODUCTION 3-Hydroxy-methylglutaryl coenzyme-a reductase inhibitors (statins) improve survival following pelvic irradiation for cancer. Large studies suggest that patients with hypertension may have reduced gastrointestinal (GI) toxicity. Animal data suggest that statins and ACE inhibitors (ACEi) may protect against normal tissue injury. Their efficacy in humans has not been reported. AIMS/METHODS To evaluate the impact of statins and ACEi on normal tissue toxicity during radical pelvic radiotherapy. GI symptomatology was recorded prospectively before radiotherapy, weekly during treatment and 1 year later using the inflammatory bowel disease questionnaire-bowel (IBDQ-B) subset. Cumulative acute toxicity (IBDQ-B AUC) and worst score were determined. Dose, brand and duration of statin and/or ACEi usage were obtained from General Practitioners. RESULTS Of 308 patients recruited, 237 had evaluable acute drug and toxicity data and 164 had data at 1year. Acutely, 38 patients (16%) were taking statins, 39 patients (16.5%) were taking ACEi and 18 patients (7.6%) were taking statin+ACEi. Mean changes in acute scores were 7.3 points (non-statin users), 7.3 (non-ACEi users) and 7.0 (non-statin+ACEi users) compared to 4.8 points (statin users), 5.0 points (ACEi users) and 4.9 points (statin+ACEi users). Statin use (p=0.04) and combined statin+ACEi use (p=0.008) were associated with reduced acute IBDQ-B AUC after controlling for baseline scores (ANOVA). At 1 year, users maintained higher IBDQ-B scores than non-users in all user subgroups. CONCLUSION Use of statin or statin+ACEi medication during radical pelvic radiotherapy significantly reduces acute gastrointestinal symptoms scores and also appears to provide longer-term sustained protection.

Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist

New gastrointestinal symptoms are frequent after pelvic radiotherapy and can greatly affect the quality of life of cancer survivors. The effect of radiation on the intestinal microbiota, and the clinical implications of a modified microbial balance after radiotherapy are now beginning to emerge. In this Personal View, we show the importance of the microbiota for intestinal homoeostasis, and discuss the similarity between inflammatory bowel disease, which has been extensively researched, and radiation-induced gastrointestinal toxicity. By use of microbiota profiles for risk assessment and manipulation of the intestinal flora for prevention and treatment of radiation, enteropathy could become a reality and would be of substantial relevance to the increasing numbers of long-term cancer survivors.

Manipulating the consequential effect: an alternative approach to reducing pelvic radiation disease other than dose reduction.

The burden of cancer doubled globally between 1975 and 2000. An estimated 12.7 million new cancer cases and 7.6 million cancer deaths occurred in 2008 [1]. The good news is that the likelihood of surviving cancer has increased two-fold to three-fold over the same period, and survival in the UK is projected to continue to increase by 3% a year [2], but in the USA, for example, it has increased at a much faster rate in recent years.

Managing gastrointestinal symptoms after cancer treatment: a practical approach for gastroenterologists

The percentage of the population living with a diagnosis of cancer is rising. By 2030, there will be 4 million cancer survivors in the UK. One quarter of cancer survivors are left with physical symptoms, which affect their quality of life. Gastrointestinal (GI) symptoms are the most common of all chronic physical side-effects of cancer treatment and have the greatest impact on daily activity. Cancer therapies induce long-term changes in bowel function due to alterations to specific GI physiological functions. In addition, the psychological effect of a cancer diagnosis, new GI disease or pre-existing underlying conditions, may also contribute to new symptoms. Twenty-three upper GI symptoms have been identified as occurring after pelvic radiotherapy. After upper GI cancer treatment, the most troublesome symptoms include reflux, abdominal pain, indigestion, diarrhoea and fatigue. Often, several symptoms are present simultaneously and women experience more symptoms than men. The symptoms which patients rate as most difficult are urgency, wind, diarrhoea, incontinence, abdominal pain and rectal bleeding. Recent UK Guidance on managing GI symptoms suggests that these symptoms can be treated especially if gastroenterological advice is combined with dietetic and nursing input to optimise investigations and management. However, as different pathological processes can result in identical symptoms; a systematic, ‘algorithmic’ approach to assess and treat these symptoms is required. This paper aims to illustrate the value of such an approach to investigate and treat the most common GI symptoms that trouble patients. The algorithm allows clinicians to institute a comprehensive medical management plan.

Randomized controlled trial of dietary fiber for the prevention of radiation-induced gastrointestinal toxicity during pelvic radiotherapy

Background: Therapeutic radiotherapy is an important treatment of pelvic cancers. Historically, low-fiber diets have been recommended despite a lack of evidence and potentially beneficial mechanisms of fiber.Objective: This randomized controlled trial compared low-, habitual-, and high-fiber diets for the prevention of gastrointestinal toxicity in patients undergoing pelvic radiotherapy.Design: Patients were randomly assigned to low-fiber [≤10 g nonstarch polysaccharide (NSP)/d], habitual-fiber (control), or high-fiber (≥18 g NSP/d) diets and received individualized counseling at the start of radiotherapy to achieve these targets. The primary endpoint was the difference between groups in the change in the Inflammatory Bowel Disease Questionnaire-Bowel Subset (IBDQ-B) score between the starting and nadir (worst) score during treatment. Other measures included macronutrient intake, stool diaries, and fecal short-chain fatty acid concentrations.Results: Patients were randomly assigned to low-fiber (n = 55), habitual-fiber (n = 55), or high-fiber (n = 56) dietary advice. Fiber intakes were significantly different between groups (P < 0.001). The difference between groups in the change in IBDQ-B scores between the start and nadir was not significant (P = 0.093). However, the change in score between the start and end of radiotherapy was smaller in the high-fiber group (mean ± SD: -3.7 ± 12.8) than in the habitual-fiber group (-10.8 ± 13.5; P = 0.011). At 1-y postradiotherapy (n = 126) the difference in IBDQ-B scores between the high-fiber (+0.1 ± 14.5) and the habitual-fiber (-8.4 ± 13.3) groups was significant (P = 0.004). No significant differences were observed in stool frequency or form or in short-chain fatty acid concentrations. Significant reductions in energy, protein, and fat intake occurred in the low- and habitual-fiber groups only.Conclusions: Dietary advice to follow a high-fiber diet during pelvic radiotherapy resulted in reduced gastrointestinal toxicity both acutely and at 1 y compared with habitual-fiber intake. Restrictive, non-evidence-based advice to reduce fiber intake in this setting should be abandoned. This trial was registered at clinicaltrials.gov as NCT 01170299.