Jervoise Andreyev

Gastrointestinal symptoms after pelvic radiotherapy: a new understanding to improve management of symptomatic patients

Gastrointestinal symptoms after pelvic radiotherapy, which affect quality of life, are substantially more common than generally recognised and are frequently poorly managed. These symptoms develop because radiation can induce change in one or more specific physiological functions in widely separated parts of the gastrointestinal tract that lie in the path of the radiotherapy beam. Radiation-induced changes are not confined by normal anatomical boundaries. Furthermore, pre-existing subclinical disease might be destabilised because of minor gastrointestinal changes induced by radiotherapy. New diseases might manifest after radiotherapy and be confused with symptoms induced by radiotherapy. Different functional deficits might cause the same symptoms. Many patients have more than one cause for their symptoms, which sometimes need very different treatments. Simple diagnostic tests that are used in other contexts, if applied appropriately to patients with new gastrointestinal symptoms after radiotherapy, can identify the underlying causes of new-onset symptoms. Starting treatment without knowing the cause of the symptom is commonly ineffective because prediction of the combination of treatments needed is difficult. Evidence suggests that many patients have unusual but highly treatable malfunctions of gastrointestinal physiology, which if correctly diagnosed may enable a patient with difficult symptoms to be helped.

Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases

Background: The role of palliative resection of the primary tumour in patients who present with metastatic colorectal cancer is unclear. Aims: This study compared the incidence of major intestinal complications in such patients who received chemotherapy treatment with or without prior palliative resection of the primary tumour. Patients: The incidence of intestinal obstruction, perforation, fistula formation, and gastrointestinal haemorrhage, and the requirement for abdominal radiotherapy in patients with metastatic colorectal cancer treated at a single institution over a 10 year period was determined. Results: Eighty two patients received initial treatment with chemotherapy without resection of the primary tumour (unresected group) and 280 patients had undergone prior resection (resected group). In the unresected group, the incidence of peritonitis, fistula formation, and intestinal haemorrhage was 2.4% (95% confidence interval (CI) 0.3–8.5%), 3.7% (95% CI 0.8–10.3%), and 3.7% (95% CI 0.8–10.3%), respectively, and was not significantly different from the resected group. Intestinal obstruction affected 13.4% (95% CI 6.9–22.7%) of patients in the unresected group and 13.2% (95% CI 9.2–17.2%) of patients in the resected group. More patients in the unresected group required ⩾3 blood transfusions (14.6% v 7.5%; p=0.048) and abdominal radiotherapy (18.3% v 9.6%; p=0.03) than the resected group. Conclusions: The incidence of major intestinal complications in patients with unresected colorectal cancer and synchronous metastases who receive initial treatment with chemotherapy is low. Chemotherapy may be successfully used as initial treatment for such patients with no increased risk of most major intestinal complications compared with patients who have undergone initial resection of the primary tumour.

Guidance on the management of diarrhoea during cancer chemotherapy

Diarrhoea induced by chemotherapy in cancer patients is common, causes notable morbidity and mortality, and is managed inconsistently. Previous management guidelines were based on poor evidence and neglect physiological causes of chemotherapy-induced diarrhoea. In the absence of level 1 evidence from randomised controlled trials, we developed practical guidance for clinicians based on a literature review by a multidisciplinary team of clinical oncologists, dietitians, gastroenterologists, medical oncologists, nurses, pharmacist, and a surgeon. Education of patients and their carers about the risks associated with, and management of, chemotherapy-induced diarrhoea is the foundation for optimum treatment of toxic effects. Adequate--and, if necessary, repeated--assessment, appropriate use of loperamide, and knowledge of fluid resuscitation requirements of affected patients is the second crucial step. Use of octreotide and seeking specialist advice early for patients who do not respond to treatment will reduce morbidity and mortality. In view of the burden of chemotherapy-induced diarrhoea, appropriate multidisciplinary research to assess meaningful endpoints is urgently required.

Organ-specific management and supportive care in chronic graft-versus-host disease

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology and the British Society for Bone Marrow Transplantation has reviewed the available literature and made recommendations for the supportive care and management of organ‐specific complications of chronic graft‐versus‐host disease (cGvHD). This guideline includes recommendations for the specific therapy of skin, oral, liver, gut, lung, ocular and genital manifestations of cGvHD and for the supportive care of these patients, including vaccinations and prophylaxis against infection. The goal of treatment should be effective control of GvHD while minimizing the risk of toxicity and relapse.

A comparison of dose–volume constraints derived using peak and longitudinal definitions of late rectal toxicity

BACKGROUND AND PURPOSE Accurate reporting of complications following radiotherapy is an important part of the feedback loop to improve radiotherapy techniques. The definition of toxicity is normally regarded as the maximum or peak (P) grade of toxicity reported over the follow-up period. An alternative definition (integrated longitudinal toxicity (ILT)) is proposed which takes into account both the severity and the duration of the complication. METHODS AND MATERIALS In this work, both definitions of toxicity were used to derive dose-volume constraints for six specific endpoints of late rectal toxicity from a cohort of patients who received prostate radiotherapy in the MRC RT01 trial. The dose-volume constraints were derived using ROC analysis for 30, 40, 50, 60, 65 and 70 Gy. RESULTS Statistically significant dose-volume constraints were not derived for all dose levels tested for each endpoint and toxicity definition. However, where both definitions produced constraints, there was generally good agreement. Variation in the derived dose-volume constraints was observed to be larger between endpoints than between the two definitions of toxicity. For one endpoint (stool frequency (LENT/SOM)) statistically significant dose-volume constraints were only derived using ILT. CONCLUSIONS The longitudinal definition of toxicity (ILT) produced results consistent with those derived using peak toxicity and in some cases provided additional information which was not seen by analysing peak toxicity alone.

The Detection of Patients at Risk of Gastrointestinal Toxicity during Pelvic Radiotherapy by Electronic Nose and FAIMS: A Pilot Study

It is well known that the electronic nose can be used to identify differences between human health and disease for a range of disorders. We present a pilot study to investigate if the electronic nose and a newer technology, FAIMS (Field Asymmetric Ion Mobility Spectrometry), can be used to identify and help inform the treatment pathway for patients receiving pelvic radiotherapy, which frequently causes gastrointestinal side-effects, severe in some. From a larger group, 23 radiotherapy patients were selected where half had the highest levels of toxicity and the others the lowest. Stool samples were obtained before and four weeks after radiotherapy and the volatiles and gases emitted analysed by both methods; these chemicals are products of fermentation caused by gut microflora. Principal component analysis of the electronic nose data and wavelet transform followed by Fisher discriminant analysis of FAIMS data indicated that it was possible to separate patients after treatment by their toxicity levels. More interestingly, differences were also identified in their pre-treatment samples. We believe these patterns arise from differences in gut microflora where some combinations of bacteria result to give this olfactory signature. In the future our approach may result in a technique that will help identify patients at “high risk” even before radiation treatment is started.

A systematic review: effectiveness of rectal emptying preparation in prostate cancer patients.

While the importance of a consistent rectal volume during radiation therapy planning and treatment for patients receiving radiation therapy to the prostate is recognized, there is no clear guidance as to the most effective method. This review examines the evidence for the efficacy of rectal preparations. Eighteen papers were found where the primary aim was to investigate a rectal emptying intervention and included 5 different strategies. These included evacuation techniques, dietary interventions, laxatives, and enemas and were either investigated alone or in combination. There is no robust evidence to recommend one rectal emptying strategy over another. Further investigation in adequately powered clinical trials is advised.

Improving the well-being of men by Evaluating and Addressing the Gastrointestinal Late Effects (EAGLE) of radical treatment for prostate cancer: study protocol for a mixed-method implementation project

Introduction Radiotherapy treatment for prostate cancer can cause bowel problems, which may lead to severe difficulties for cancer survivors including limiting travel, work or socialising. These symptoms can appear at any time following radiotherapy. This study focuses on the early identification and protocol-based management of effects known to cause long-term, or even permanent, changes to the well-being of prostate cancer survivors. The rationale of this study is to improve the care offered to men and their families following pelvic radiotherapy for prostate cancer. Method and analysis Implementation research methodology will be used to adopt a multicomponent intervention at three UK centres. The intervention package comprises a standardised clinical assessment of relevant symptoms in oncology outpatient clinics and rapid referral to an enhanced gastroenterological service for patients identified with bowel problems. Gastroenterology staff will be trained to use an expert-practice algorithm of targeted gastroenterology investigations and treatments. The evaluation of the intervention and its embedding within local practices will be conducted using a mixed-methods design. The effect of the new service will be measured in terms of the following outcomes: acceptability to staff and patients; quality of life; symptom control and cost-effectiveness. Data collection will take place at baseline, 6 months (±2 months), and 12 months (±2 months) after entry into the study. Ethics and dissemination The study has ethical approval from the North West-Liverpool East Research Ethics Committee and the appropriate NHS governance clearance. All participants provide written informed consent. The study team aim to publish the results of the study in peer-reviewed journals as well as at national and international conferences. Trial registration number UKCRN16974

CD4-positive small T-cell lymphoma of the intestine presenting with severe bile-acid malabsorption: a supportive symptom control approach

The only primary intestinal T-cell lymphomas (ITCL) recognized as distinct entities by the World Health Organization (WHO) classification are enteropathy-associated T-cell lymphoma types I and II (EATL I and II). Other T-cell lymphomas may involve or arise in the intestine but tend to occur without enteropathy (Isaacson et al, 2008). More recently, several indolent T-cell/Natural killer (NK) cell proliferations have been described but have yet to be acknowledged as distinct entities. Twenty cases of a distinct ITCL associated with sprue-like symptoms have been reported, showing a lymphomatous infiltrate of small, mildly atypical CD4/CD8 lymphoid cells occupying the lamina propria, rarely infiltrating the epithelium and having a strikingly benign clinical course (Carbonnel et al, 1994, 1999; Zivny et al, 2004; Svrcek et al, 2007; Margolskee et al, 2013; Perry et al, 2013 and Malamut et al, 2014). We report an additional case of a 59-year-old Afro-Caribbean female patient evaluated for a 1-year history of diarrhoea and moderate weight loss. Duodenal biopsies were considered consistent with coeliac disease. A gluten-free diet was implemented with no symptomatic improvement. Serological investigations (anti-endomysial and anti-gliadin antibodies) were negative. Computerized tomography (CT) and positron-emission tomography (PET)-CT scans showed slightly enlarged, mildly hypermetabolic mesenteric lymph nodes with no evidence of disease outside the gastrointestinal tract (GIT). Full blood count and routine biochemistry revealed mild anaemia and slightly increased lactate dehydrogenase levels. Duodenal biopsies revealed sub-total villous atrophy, diffuse mucosal infiltration by monomorphic small T-cells with scanty cytoplasm and irregular nuclei, and a patchy increase in intra-epithelial lymphocytes (30–40 IEL/100 enterocytes). Immunoprofile was CD2/CD3/CD4/CD7/ CD8 /CD56 /CD103 /TCR-b+ with absence of cytotoxic granules or a follicular T-helper phenotype (Fig 1). Gastric and colonic biopsies showed a similar T-cell infiltrate. Polymerase chain reaction detected clonal TRB and TRG rearrangements, which were identical in all samples examined. Bone marrow biopsy and aspirate were negative for lymphoma. The patient was treated with six cycles of gemcitabine and methylprednisolone (Gem-P) with mild, transient symptomatic improvement and an unchanged neoplastic infiltrate in the duodenum throughout the five sequential samples analysed. Further investigations revealed severe bile acid (BA) malabsorption [Tauroselcholic (75 selenium) acid retention of 4%] and mild pancreatic insufficiency. The patient was successfully managed with dietary changes (reduced fat intake), Colesevelam hydrochloride 625 mg and Creon 10 000 lipase units, with major improvement in previously reported GI symptoms and stable weight. The most recent WHO Classification recognizes EATL as the only distinct type of primary ITCL showing a poor response to chemotherapy, severely debilitated patients and dismal prognosis (Isaacson et al, 2008; Perry et al, 2013). Carbonnel et al (1994) described a low-grade ITCL with peculiar clinical, morphological and immunophenotypic features. Nineteen further cases with remarkably homogeneous characteristics have been described. They shared similar symptoms and most were initially diagnosed as coeliac disease but failed to improve with gluten-free diet. Morphologically, intestinal lamina propria is prominently infiltrated by small pleomorphic lymphocytes with low-grade cytology, with mild alterations in crypt architecture, normal/ slightly raised IEL count and rare lymphoepithelial lesions (Carbonnel et al, 1999; Margolskee et al, 2013). All cases had a CD4/CD8 immunophenotype (Table I). Including our case, the majority of patients were male (13 males, 8 females) with a median age of 50 5 (range 22–68) years, and a 4–240-month interval between initial symptoms and diagnosis. Mean follow up was 6 4 (1 4–19 8) years. Excluding one case [reported by Malamut et al (2014), which showed complete histological remission (CHR) after treatment with anti-CD52 monoclonal antibody], the vast majority failed to achieve CHR. Three patients died, one with complications related to bowel obstruction; another following large cell transformation, sepsis and small bowel perforation and the third with progressive multifocal leucoencephalopathy (Carbonnel et al, 1999; Margolskee et al, 2013; Table I). Other indolent T-cell lymphomas primarily affecting the GIT, with similar morphologic and immunophenotypic features, have been reported. However, there were different clinical manifestations, including multiple polypoid lesions (Hirakawa et al, 1996), colonic aphthous ulcers (Egawa et al, 1995) and CD103expression, which was consistently negative correspondence

Challenging current views on bile acid diarrhoea and malabsorption

Background In 2012, the National Institute for Health and Care Excellence (NICE) assessed guidance (DG7) on the use of tauroselcholic (75selenium) acid (also known as SeHCAT) for the investigation of diarrhoea due to bile acid malabsorption (BAM) in patients with IBS-D and in patients with Crohn’s disease who have not had an ileal resection. NICE concluded that tauroselcholic (75selenium) acid was recommended for use in research only. NICE will be reviewing the decision to update the guidance for tauroselcholic (75selenium) acid, for these populations, in March 2017. Aim Our aim is to summarise advances in BAM, also known as bile acid diarrhoea (BAD), and encourage clinicians to re-evaluate their understanding of this disorder. Approach We review the prevalence, diagnosis and treatment of BAD/BAM. We describe the new evidence available since the original NICE review in 2012, and discuss the economic issues associated with failure to diagnose or to treat BAD/BAM accurately. Evidence update There is new and compelling evidence available since DG7, which shows that tauroselcholic (75selenium) acid scanning is a powerful tool in the diagnosis of BAD/BAM. We summarise published prevalence data (approximately 1% prevalence in the UK, as suggested by clinical practice diagnosis rates), and highlight that the true prevalence of BAD/BAM could be far greater than this. Conclusion We present evidence that challenges current opinion about this disorder, and we commend both clinicians and health technology assessment (HTA) agencies for being open to arguments and new evidence in any future HTAs.