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Gastrointestinal Complications of Oncologic Therapy Marta Davila and Robert S Bresalier*

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Gastrointestinal Complications of Oncologic Therapy Marta Davila and Robert S Bresalier* REVIEW REVIEW www.nature.com/clinicalpractice/gasthep Gastrointestinal complications of oncologic therapy Marta Davila and Robert S Bresalier* SUMMARY INTRODUCTION Various nonsurgical oncologic treatments are Gastrointestinal complications are common in patients undergoing currently available, including chemotherapy, various forms of cancer treatment, including chemotherapy, radiation radiotherapy, and molecular-targeted thera- therapy, and molecular-targeted therapies. Many of these complications pies. Although many oncologic treatments are are life-threatening and require prompt diagnosis and treatment. effective, they frequently have adverse effects, a Complications of oncologic therapy can occur in the esophagus considerable number of which affect the gastro- (esophagitis, strictures, bacterial, viral and fungal infections), upper intestinal tract. Any part of the gastrointestinal gastrointestinal tract (mucositis, bleeding, nausea and vomiting), colon tract can be affected, including the esophagus (diarrhea, graft–versus–host disease, colitis and constipation), liver (drug hepatotoxicity and graft–versus–host disease), and pancreas (esophagitis, strictures, bacterial, viral and fungal (pancreatitis). Treatment of the different gastrointestinal complications infections), upper gastrointestinal tract (muco- should be tailored to the individual patient and based on the underlying sitis, bleeding, nausea and vomiting), colon (diar- pathophysiology of the complication. rhea, graft–versus–host disease [GVHD], colitis and constipation), liver (drug hepatotoxicity and KEYWORDS drug hepatotoxicity, drug-induced enterotoxicity, graft–versus–host disease, infectious esophagitis, neutropenic enterocolitis GVHD), and pancreas (pancreatitis). Many of these gastrointestinal adverse effects differ in REVieW criteria severity between individuals, but they can be life- A thorough literature search was performed using MEDLINE/PubMed threatening and must be quickly identified and search engines with secondary review of cited publications. Prospective and treated. In some instances, oncologic treatment retrospective studies, clinical trials as well as review articles were included. The following key terms were used for selection of articles: “esophagitis”, “esophageal will need to be adjusted to minimize the develop- strictures”, “drug-induced diarrhea”, “Clostridium difficile colitis”, “neutropenic ment of severe gastrointestinal complications. enterocolitis”, “constipation”, “graft versus host disease”, “radiation proctitis” Monitoring of the oncologic treatment for each and “drug-induced liver toxicity” and “liver injury”, “chemotherapy-induced patient in relation to associated adverse effects nausea and vomiting”, “mucositis”. The search was performed in January 2008 for is, therefore, essential and requires efficient references published in 1970 and later, and was restricted to full papers in English. communication between oncologists and gastro- enterologists to ensure that the most effective oncologic treatment is administered whilst any gastrointestinal adverse effects are managed. This Review discusses some of the gastro- intestinal complications that can arise as a result of various oncologic treatments, including esophagitis, diarrhea and constipation, neutro- penic enterocolitis, GVHD, radiation proctitis, drug hepatotoxicity, nausea and vomiting, gastro- intestinal perforation, fistula formation, arterial M Davila is an Associate Professor and RS Bresalier is Professor of Medicine thrombosis and bleeding, acute pancreatitis, and in the Department of Gastroenterology, Hepatology and Nutrition at the MD oral mucositis. The pathologic mechanisms Anderson Cancer Center, Houston, TX, USA. underlying each complication are discussed, along with the symptoms, methods of diagnosis Correspondence *Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD and treatment options. Anderson Cancer Center, 1515 Holcombe Boulevard Unit 436, Houston, TX 77030-4009, USA [email protected] ESOPHAGITIS Esophagitis in patients with cancer can be caused Received 16 May 2008 Accepted 11 September 2008 Published online 21 October 2008 www.nature.com/clinicalpractice by the cytotoxic effects of chemotherapy and doi:10.1038/ncpgasthep1277 radiation, or by infection with viral, fungal or 682 NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY DECEMBer 2008 Vol 5 no 12 REVIEW REVIEW www.nature.com/clinicalpractice/gasthep Table 1 Common causes of esophagitis in patients receiving oncologic therapy. Causative agent Diagnosis Symptoms Endoscopic/histologic Treatment appearance Candida albicans Endoscopy, Odynophagia, dysphagia White plaque-like lesions, Systemic antifungal biopsy surrounding erythema on treatment (e.g. fluconazole, esophageal walls itraconazole, voriconazole, echinocandins) HSV Endoscopy, Odynophagia, dysphagia, nausea, Small vesicles, coalescing Aciclovir, foscarnet sodium biopsy, IHC vomiting, heartburn, epigastric pain, to form ulcers fever. Symptoms of coexistent herpes labialis or presence of oropharyngeal ulcers CMV Endoscopy, Odynophagia, dysphagia, nausea, Linear or serpiginous ulcers Intravenous ganciclovir, biopsy vomiting, heartburn, epigastric pain, foscarnet sodium fever VZV Endoscopy, Odynophagia, dysphagia, nausea, Ulcers similar to HSV ulcers Intravenous aciclovir biopsy vomiting, heartburn, epigastric pain, fever. Symptoms of coexistent disseminated herpes zoster Polymicrobial, Endoscopy, Odynophagia, dysphagia Clusters of bacteria mixed Broad-spectrum antibiotics oral flora biopsy, with necrotic epithelial cells in biopsy samples Radiation treatment Endoscopy Odynophagia, dysphagia, chest pain Erythema, edema and Lidocaine hydrochloride, (e.g. of lung friability of the mucosa; PPIs, endoscopic dilation, and esophageal ulcerations, stricture SEPS cancers) formation Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; IHC, immunohistochemistry; SEPS, self-expanding plastic stents; VZV, varicella-zoster virus. bacterial organisms (Table 1), the risk of which is surrounding erythema covering the esophageal often increased in immunocompromised cancer walls. Esophageal biopsies or brushings should patients.1 Other causes of esophagitis that are be taken and used to confirm the presence of common in patients with cancer include GERD, invasive yeast or hyphal forms of C. albicans. pill-induced injury, and GVHD in hemato- Treatment of esophageal candidiasis in poietic stem-cell transplant recipients. Prompt immunocompromised patients requires sys- endoscopic evaluation and biopsies are recom- temic antifungal therapy, and it should never mended when esophagitis is suspected in an be managed with topical agents in this setting. immunocompromised patient, to enable early Fluconazole (100–200 mg daily for 14–21 days) is diagnosis and therapy.2 effective at eradicating Candida infections and is the treatment of choice for most patients with Fungal infections esophageal candidiasis.3 Itraconazole oral solu- Esophageal candidiasis is one of the most tion (200 mg daily) and voriconazole (200 mg common infections in immunocompromised twice daily) might be as effective as flucon- patients, and is most often caused by Candida azole.4,5 Voriconazole can be used for the treat- albicans. Patients with esophageal candidiasis ment of infections unresponsive or refractory to usually complain of odynophagia and/or dys- fluconazole therapy.6 Itraconazole use has been phagia. Of note, the absence of oropharyngeal associated with considerable nausea and has the thrush does not exclude a diagnosis of esophageal potential to interact with other drugs because it candidiasis. An empiric trial of antifungal therapy inhibits the cytochrome p450 enzymatic system. is appropriate when patients present with classic The echinocandins—caspofungin, micafungin symptoms such as odynophagia and/or dys- and anidulafungin—are also very effective for phagia, but endoscopy should be performed and the treatment of Candida esophagitis.7–9 They biopsy samples taken if symptoms do not improve are administered intravenously and are used to approximately 72 h after treatment initiation.1 a larger extent in hospitalized patients. Another On endoscopy, esophageal candidiasis is antifungal drug, amphotericin B, is no longer identified by white plaque-like lesions with recommended because of its toxicity profile. DECEMBer 2008 Vol 5 no 12 DAVILA AND BRESALIER NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY 683 REVIEW REVIEW www.nature.com/clinicalpractice/gasthep Viral infections hydrolyzed to ganciclovir. Although val- Viral infections of the esophagus are caused by ganciclovir has been approved for the treat- herpes simplex virus (HSV), cytomegalovirus ment of CMV retinitis in patients with AIDS (CMV), and rarely, varicella-zoster virus (VZV). and is used for prophylaxis against CMV infec- Presenting symptoms include odynophagia, tion in solid-organ transplant recipients, its role dysphagia, and less frequently nausea, vomiting, in CMV gastrointestinal disease has not been heartburn, epigastric pain and fever. Some patients studied. At a dose of 900 mg daily, valganciclovir with HSV esophagitis might have coexistent produces systemic exposure to a dose equivalent herpes labialis or oropharyngeal ulcers.10 to that of intravenous ganciclovir at 5 mg/kg.15 Diagnosis of esophageal viral infection is by Anecdotal reports suggest that oral val- endoscopy and biopsy. In the early stage of infec- ganciclovir can effectively treat
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