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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 , various forms of 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 considerable number of which affect the gastro- (, strictures, bacterial, viral and fungal infections), upper intestinal tract. Any part of the gastrointestinal (mucositis, bleeding, and vomiting), colon tract can be affected, including the esophagus (, graft–versus–host disease, and ), liver (drug hepatotoxicity and graft–versus–host disease), and pancreas (esophagitis, strictures, bacterial, viral and fungal (). 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 . 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 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 ” 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, , drug hepatotoxicity, nausea and vomiting, gastro­ intestinal perforation, formation, arterial M Davila is an Associate Professor and RS Bresalier is Professor of Medicine thrombosis and bleeding, , and in the Department of , 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

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Table 1 Common causes of esophagitis in patients receiving oncologic therapy. Causative agent Diagnosis Symptoms Endoscopic/histologic Treatment appearance albicans Endoscopy, , White plaque-like lesions, Systemic antifungal surrounding erythema on treatment (e.g. , esophageal walls , 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 ) formation Abbreviations: CMV, cytomegalovirus; HSV, 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 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 or hyphal forms of C. albicans. pill-induced injury, and GVHD in hemato­ Treatment of esophageal 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 .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—, symptoms such as odynophagia and/or dys­ and —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, , is no longer identified by white plaque-like lesions with recommended because of its toxicity profile.

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Viral infections hydrolyzed to ganciclovir. Although val­ Viral infections of the esophagus are caused by ganciclovir has been approved for the treat- (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 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 CMV esopha- tion, HSV lesions can appear as small vesicles; gitis once odynophagia has been improved by these eventually coalesce to form large ulcers that intravenous ganciclovir, and patients can toler­ are usually less than 2 cm in size.11 CMV causes ate oral medication. Other groups have sug- ulcers that are linear or serpiginous and deeper gested that oral valganciclovir should be used as than HSV-related ulcers. VZV can produce maintenance therapy in patients who have had a esophagitis in adults with herpes zoster, usually relapse of CMV infection in the gastrointestinal in the setting of disseminated infection.2 tract. Additional studies are, however, needed Endoscopically, VZV ulcers are similar to to make specific recommendations concerning those caused by HSV, and distinction requires the use of valganciclovir for the treatment of immunohistochemistry or culture of biopsy CMV esophagitis. specimens. Biopsy samples taken from the edge of an HSV-related ulcer will show intra- Bacterial infections nuclear inclusions and multinucleated giant Bacterial esophagitis can occur in immuno­ cells. Inclusions can also be detected by compromised patients and is usually polymicro- immunohistochemistry, by using monoclonal bial, being derived from oral flora.2 Diagnosis is antibodies to HSV. Biopsy samples taken from made by endoscopic biopsies that demonstrate the patients with CMV infection show intranuclear presence of bacteria clusters mixed with necrotic inclusions in fibroblasts and endothelial cells. epithelial cells. Treatment with broad-spectrum Immunohistochemistry with anti-CMV antibodies antibiotics is usually successful. is also helpful for diagnosis. For patients with HSV esophagitis, aciclovir Radiation-induced esophagitis (400 mg orally five times daily for 14–21 days or Radiation-induced esophagitis can occur during 5 mg/kg intravenously every 8 h for 7–14 days) radiation treatment of lung and esophageal is the therapy of choice. Foscarnet sodium is cancers. The severity of esophagitis gener- reserved for those patients infected with aciclovir- ally increases with radiation dose and with the resistant HSV strains or those who do not respond combined use of some chemotherapeutic agents to aciclovir treatment. Famciclovir or valaciclovir such as doxorubicin hydrochloride, bleomycin, can be considered in patients able to tolerate cyclophosphamide and cisplatin.16,17 oral therapy, although there is limited clinical Patients with radiation-induced esophagitis experience with these drugs for the treatment often complain of odynophagia, dysphagia, of HSV-associated esophagitis. and chest pain. Endoscopy can reveal ery- VZV esophagitis is initially treated with intra- thema, edema and friability of the mucosa, as venous aciclovir as these patients usually have well as ulcerations and stricture formation. disseminated infection. After clinical improve- Treatment includes the use of viscous lidocaine ment, patients can be switched to any of the oral hydrochloride and PPIs to prevent further agents mentioned above for HSV esophagitis. acid-related injury. CMV esophagitis can be treated with intra- Strictures are managed by endoscopic dila- venous ganciclovir (5 mg/kg twice daily) or tion, and strictures refractory to endoscopic foscarnet sodium (90 mg/kg twice daily) for dilation can be managed by the placement of 3–6 weeks.12–14 Whether maintenance treat- self-expanding plastic stents (SEPS) (Figure 1). ment is needed once the initial infection has SEPS are similar in concept to expandable been cleared is controversial. Valganciclovir metal stents, however, SEPS have the advantage is an oral agent that is rapidly absorbed and of being able to be repositioned, and removed

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once the stricture has resolved. Clinical data A B suggest that temporarily placed SEPS can be curative for esophageal strictures in up to 80% of patients who have benign esophageal lesions.18,19 The most common complication of SEPS is migration of the stent, which can occur in up to one-third of patients.20 In patients with tracheo-esophageal fistula occurring secondary to esophageal cancer, covered stents (either self- expanding metal or plastic stents) are the treat- ment of choice, and can achieve fistula closure 21 Figure 1 Use of a self-expanding esophageal stent to manage an esophageal in 70–100% of patients. stricture. (A) Endoscopic view of a self-expanding stent deployed in the esophagus. (B) Chest radiograph showing the stent deployed in the esophagus. DIARRHEA Diarrhea is a common complication of cytotoxic therapy (Box 1), and occurs most commonly in cancer patients treated with fluoropyrimidines Box 1 Common causes of diarrhea in patients (particularly 5-fluorouracil [5-FU]), irino­ receiving oncologic therapy. tecan hydrochloride, methotrexate or cisplatin. Fluoropyrimidines The diarrhea can be debilitating and in severe ■ 5-Fluorouracil cases can even be life-threatening. The onset of ■ Capecitabine diarrhea can lead to cancer treatment delays, reduced quality of life, and diminished drug Irinotecan hydrochloride compliance. In fact, diarrhea is the dose-limiting Oxaliplatin factor and the major toxic adverse effect of regi­ Small-molecule EGFR inhibitors Erlotinib mens containing a fluoropyrimidine and/or ■ irinotecan hydrochloride. Small-molecular VEGF inhibitors Other causes of diarrhea in patients under- ■ Sorafenib going cancer treatment include radiation Monoclonal antibodies directed against EGFR therapy, small-molecule therapy, monoclonal ■ Cetuximab antibody therapy, neutropenic enterocolitis, and Clostridium difficile colitis. Neutropenic Graft–versus–host disease enterocolitis is discussed separately to diarrhea Clostridium difficile infection because of its unique setting. GVHD in patients Abbreviations: EGFR, epidermal growth factor receptor; who have received an allogeneic hematopoietic VEGF; vascular endothelial growth factor. stem-cell transplant is also associated with severe diarrhea and is discussed in more detail later in the Review. is administered by bolus injection as opposed to Chemotherapy-induced diarrhea intravenous infusion. Other factors that can raise The severity of chemotherapy-induced diar- the risk of 5-FU-induced diarrhea include female rhea is often described, particularly for study sex, the presence of an unresected primary purposes, using the National Cancer Institute tumor, previous episodes of chemotherapy- Common Toxicity Criteria (NCI CTC).22 induced diarrhea, and treatment during the Grading is based on the number of stools passed summer season.23,24 per day, the passing of nocturnal stools, and the Irinotecan hydrochloride can cause an need for parenteral support or intensive care. early-onset diarrhea accompanied by abdomi- The severity and prevalence of diarrhea caused nal cramping, lacrimation, salivation, and by 5-FU treatment is increased by the addition other symptoms that seem to be mediated by of leucovorin (also known as folinic acid) to cholinergic receptors. These symptoms can be the treatment regimen. Diarrhea is reported in effectively treated with atropine as well as loper­ up to 50% of patients receiving weekly 5-FU/ amide hydrochloride.25 The late-onset diarrhea leucovorin combined treatment. Moreover, the associated with irinotecan hydrochloride is severity of the diarrhea can worsen when 5-FU unpredictable and can occur at all dose levels. It ncpgasthep_2006_255f1.eps

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is seen less frequently when irinotecan hydro- Treatment of chemotherapy-induced chloride is given every 3 weeks rather than and radiation-induced diarrhea weekly.20 Diarrhea caused by the combined The treatment of chemotherapy-induced or treatment regimen of irinotecan hydrochloride, radiation-induced diarrhea involves aggressive 5-FU and leucovorin has been reported to be oral rehydration and electrolyte replacement substantially more severe compared with diar- and the use of pharmacologic agents to reduce rhea caused by 5-FU and leucovorin without fluid loss and decrease intestinal motility. Opioid irinotecan hydrochloride.26–28 agonists are a basic component of therapy. Capecitabine is an oral fluoropyrimidine that Loperamide hydrochloride (Imodium®; Johnson is converted to 5-FU by a series of enzymatic & Johnson, New Brunswick, NJ) and diphen­ reactions. One of the major dose-limiting toxici- oxylate (Lomotil®; G.D. Searle & Co., Skokie, IL) ties of capecitabine is diarrhea. There seems to be are the agents most commonly used to treat diar- regional differences in tolerance to capecitabine, rhea. For mild-to-moderate diarrhea, an initial with more serious adverse events reported in the dose of 4 mg loperamide hydrochloride should US compared with other parts of the world.29 be given, followed by a further 2 mg every 4 h or These regional variations might be due to genetic after every stool. Severe cases of diarrhea or irino­ polymorphisms, lifestyle or possibly differences tecan-hydrochloride-induced diarrhea often in dietary folate intake.29 require a more aggressive regimen, with an initial Diarrhea also occurs frequently in patients dose of 4 mg loperamide hydrochloride followed with cancer treated with regimens combin- by a further 2 mg every 2 h or 4 mg every 4 h until ing 5-FU, leucovorin and oxaliplatin, particu- the patient has been diarrhea-free for 12 h.36,37 larly when 5-FU is administered as a weekly or Octreotide—a synthetic long-acting somato­ daily bolus.30,31 statin analog—has been used as second-line therapy in patients who do not respond to Diarrhea induced by small molecules opioids. The recommended initial dose of and monoclonal antibodies octreotide is 100–150 µg given subcutaneously Diarrhea is also common in patients with cancer three times daily, or 25–50 µg every hour if given receiving small-molecule epidermal growth as an intravenous infusion.37 Octreotide can be factor receptor (EGFR) tyrosine kinase inhibi- titrated to higher doses (500–2,500 µg three times tors. For example, grade 1–2 diarrhea as defined daily) for the treatment of those individuals by the NCI CTC has been reported in up to who do not respond to lower doses.38,39 56% of patients receiving erlotinib.32 Another Other agents have been used as adjunctive small-molecule inhibitor of tyrosine kinases in therapy in the treatment of mild-to-moderate the vascular endothelial growth factor (VEGF) chemotherapy-induced and radiation-induced pathway, sorafenib, has been associated with diarrhea, including absorbents such as kaolin diarrhea in approximately 34% of patients.33 and charcoal, deodorized tincture of opium, Unlike the small-molecule EGFR inhibitors, paregoric, and codeine phosphate. cetuximab, which is a chimeric monoclonal antibody that binds EGFR, has been reported Stem-cell-transplantation-associated to cause diarrhea of any grade in only 12.7% diarrhea of patients and grade 3 diarrhea in only Patients undergoing stem-cell transplantation can 1.2% of patients.34 suffer from diarrhea caused by the conditioning regimen, GVHD or to an infection related to Radiation-induced diarrhea immunosuppressive therapy. Pretransplant con- Radiation therapy can injure the gastrointestinal ditioning regimens (including total body irradia- mucosa. The extent of injury and associated tion and/or a combination of chemotherapeutic diarrhea usually peaks 1–2 weeks after initiation agents) can injure the intestinal mucosa as dis- of irradiation. Worsening diarrhea occurs when cussed above, causing a secretory diarrhea that radiation is given in combination with chemo- resolves after mucosal restitution. Recipients of therapy, for example with 5-FU for the treatment allogeneic stem-cell transplants can also develop of rectal cancer.35 Patients presenting with severe GVHD, which usually starts 3 weeks or longer diarrhea, fever or neutropenia following chemo- after transplantation. GVHD and its associated radiation should be admitted to hospital for a diarrhea are discussed in a separate section in diagnostic work-up and treatment. more detail.

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Clostridium difficile diarrhea However, has some advantages C. difficile infection is the most common cause over vancomycin including its lower cost and of infectious diarrhea in hospitalized patients.40 the fact that it can reduce selection of vanco- Although commonly associated with the mycin-resistant enterococci. Metronidazole use of antibiotics, risk factors for C. difficile is, therefore, considered by many to be the colitis also include bowel , an immuno­ initial therapy of choice in nonsevere cases of compromised state and any process that sup- C. difficile-induced diarrhea. presses the normal gastrointestinal flora, In patients with severe C. difficile infec- including chemotherapeutic agents. tion and signs of systemic toxicity, the recom- Patients with cancer undergoing chemotherapy mended treatment regimen is initial therapy are also predisposed to C. difficile-induced diar- with vancomycin 125 mg orally four times rhea even in the absence of antibiotic therapy.41 daily, with escalation of the dose at 48 h inter- Use of methotrexate, doxorubicin hydrochloride vals up to 500 mg four times daily if patients fail and cyclophosphamide is frequently associated to improve. If patients do not respond to oral with C. difficile infection.41 Clinical presenta- vancomycin, the addition of intravenous metro- tion of C. difficile infection can vary from mild nidazole 500 mg every 8 h, or vancomycin reten- diarrhea without colitis, to colitis with systemic tion (0.5–1 g of vancomycin dissolved manifestations, pseudomembranous colitis in 1–2 l of normal saline every 4–12 h), should with or without protein-losing , be considered.46 or fulminant colitis with the development of Relapse of C. difficile-induced diarrhea is toxic . common, occurring in up to 10–25% of all A diagnosis of C. difficile-related diarrhea is patients with C. difficile infection. Relapses established by detecting the presence of C. diffi­ usually occur within 1–3 weeks after termi- cile toxin in stool or by identifying pseudo­ nation of initial therapy, and are probably membranous colitis on endoscopic evaluation caused by failure to eradicate the organism (Figure 2). Endoscopically, pseudomembranes rather than development of antibiotic resis- can be seen as adherent yellow plaques that vary in tance.40 First relapses should be treated with a diameter from 2 mm to 10 mm. The intervening second 10–14 day course of oral metronidazole mucosa can appear normal or mildly erythema­ or vancomycin.47 If a patient relapses after tous.40 The and are typi- taking a second course of antibiotics, differ- cally involved, but in approximately 10% of cases ent approaches have been suggested, including colitis is only present in the more proximal colon tapered or pulsed antibiotic therapy, and the use and can be missed during . of anion-binding resins such as colestyramine or The stool cytotoxin assay is a tissue culture assay colestipol hydrochloride alone or in combination based on the induction of cell rounding by C. diffi­ with vancomycin.48 cile toxin in stool filtrate, and is considered the gold standard for diagnosis. It has a high sensitiv- NEUTROPENIC ENTEROCOLITIS ity (94–100%) and specificity (99%),42 however, Neutropenic enterocolitis is a clinical syndrome it is costly and it takes 2–3 days to complete. More in neutropenic patients that is characterized by rapid and inexpensive enzyme-linked immuno- fever and right lower quadrant pain. The disease sorbent assays (ELISAs) with similar sensitiv- has been reported in children and adults with ity (70–90%) and specificity (99%) can also be leukemia, multiple myeloma, aplastic , used.43 These ELISAs detect the most common myelodysplastic syndrome, granulocytopenias enterotoxin produced by C. difficile, toxin A, but from other causes or AIDS, and after immuno- do not detect toxin B. If an initial stool immuno­ suppressive therapy for solid malignancies and assay test is negative, repeating a stool ELISA or transplants.47,49 The true incidence of neutro- supplementing it with a cytotoxicity assay can penic enterocolitis is unknown. In a systematic increase the sensitivity for diagnosis.44 review of 145 published articles, a 5.3% pooled Standard therapy for C. difficile-associated incidence rate of neutropenic enterocolitis was diarrhea is oral metronidazole or oral vanco- reported in a population that included adults mycin. Metronidazole at a dose of 500 mg three hospitalized for the treatment of hematologic times daily given either orally or intravenously malignancies or aplastic anemia or who were for 10–14 days is as effective as oral vancomycin receiving high-dose chemotherapy for the given at a dose of 125 mg four times daily.45 treatment of solid tumors.50

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A B enterocolitis. Abnormal findings on CT and ultrasound that are indicative of neutropenic enterocolitis include a fluid-filled, dilated cecum, a right lower quadrant inflammatory mass and pericecal fluid or inflammatory changes in the pericecal soft tissues.51 Plain films of the abdomen often show nonspecific findings, but they can occasionally reveal a distended cecum with dilated adjacent loops of small bowel, thumbprinting or .52 Treatment of neutropenic enterocolitis is Figure 2 Pseudomembranous colitis. (A) Plaque-like ‘pseudomembranes’ adherent to the colonic mucosa, as observed by . mostly supportive and consists of bowel rest (B) Photomicrograph of a typical lesion with a ‘volcano-like’ appearance with and the administration of intravenous fluids and luminal inflammatory exudate. broad-spectrum antibiotics.51 Cytopenias and coagulopathy associated with oncologic treatment should also be corrected since neutro­ penia contributes to the pathogenesis of the Pathogenesis and symptoms disease and coagulopathy can be associated with A combination of factors might be involved in blood loss from mucosal hemorrhage. Strong the pathogenesis of neutropenic enterocolitis, consideration should also be given to the use of including mucosal injury by cytotoxic drugs, recombinant granulocyte colony-stimulating neutropenia and impaired host defense against factor (G-CSF) to hasten leukocyte recovery, as intestinal organisms.51 Histologic examination of normalization of neutrophil counts might con- biopsy samples can reveal a thickened bowel wall, tribute to the resolution of neutropenic entero- edema, mucosal ulcerations, focal hemorrhage colitis.52,53 Surgery has been recommended for and mucosal or transmural necrosis. patients with persistent gastrointestinal bleed- Numerous bacterial and/or fungal organisms ing despite correction of cytopenias and coagulo­ have been identified in surgical specimens and pathy.52,54 Surgery is also recommended for peritoneal fluid from patients with neutropenic patients with perforation or clinical deterioration enterocolitis, including Gram-negative rod bac- despite pharmacologic therapy.52,54 teria, Gram-positive cocci, enterococci, anaer- obes (e.g. Clostridium septicum) and Candida CONSTIPATION species.49,51 Leukemic or acute inflammatory Constipation is a common problem in patients infiltrates have only rarely been identified in undergoing cancer treatment. In this setting, these patients.47 constipation is usually caused by a combination Patients with neutropenic enterocolitis present of poor oral intake, decreased physical activ- with profound neutropenia, fever and abdomi- ity, and the action of drugs such as opioid anal­ nal pain, particularly in the right lower quad- gesics or antiemetic agents, which slow intestinal rant. Other presenting symptoms can include transit time. Constipation has also been reported abdominal distension, nausea, vomiting and in patients taking vinka alkaloids, in particular watery or bloody diarrhea. vincristine and thalidomide.55,56 Impaction, and colonic Diagnosis and treatment pseudo-obstruction must be ruled out before The presentation and clinical findings of neutro- initiating therapy for constipation. Electrolyte penic enterocolitis can be nonspecific, and there- abnormalities and other reversible causes fore differential diagnoses must be considered, should be corrected first. Drugs that cause con- including pseudomembranous colitis, other stipation should be discontinued if possible. infectious colitis, colonic pseudo-obstruction, Laxatives, with or without stool softeners, can acute and . also be used in the initial treatment of constipa- A diagnosis of neutropenic enterocolitis tion. Stimulant laxatives such as bisacodyl and is usually made by performing imaging senna alter electrolyte transport by the intestinal studies—CT is preferred to ultrasound or plain mucosa and increase intestinal motor activity. abdominal films. CT is also useful in ruling out If these agents are not effective, osmotic agents other processes that can mimic neutropenic such as lactulose or sorbitol can be effective at ncpgasthep_2006_255f1.eps

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improving stool frequency and consistency.57 patients are referred for evaluation of potential Polyethylene glycol solutions (without elec- acute GVHD. trolytes) are available in powder form and have been found to be effective at improving Chronic graft–versus–host disease chronic constipation.57 The use of drugs to Chronic GVHD can occur in up to 50% of improve colonic transit has been disappoint- patients who survive long-term after receiving a ing. Metoclopramide seems to be ineffective, transplant from an HLA-identical sibling.65 The and tegaserod (a 5-hydroxytryptamine recep- esophagus is the most common site of involve- tor agonist) has been removed from the market ment in patients with chronic GVHD, and these because of concern regarding its cardiovascular patients can develop painful esophageal ulcera­ adverse effects. tions, webs, rings and strictures.66 The oral mucosa can be dry, resulting in ulceration and GRAFT–VERSUS–HOST DISEASE pain. The small bowel and colon are not as fre- GVHD is classified as either acute or chronic quently involved as in acute GVHD, but when on the basis of the time to disease onset follow- they are involved, patients can present with diar- ing transplantation. Acute GVHD disease onset rhea, , fibrosis of the submucosa occurs within the first 100 days of hematopoietic and sclerosis of the intestine.66,67 stem-cell transplantation, whereas chronic The liver is commonly involved in acute and disease is defined as disease onset after 100 days chronic GVHD. Pathology can reveal exten- following transplantation. This classification sive damage with bile duct atypia and is somewhat arbitrary because a continuum of degeneration, epithelial cell dropout and lympho­ clinical findings can be observed in patients with cytic infiltration of small bile ducts leading acute or chronic GVHD. to .68,69 Biopsy is the only method to diagnose GVHD of the liver and to rule out Acute graft–versus–host disease other entities in the differential diagnosis, such Acute GVHD has been reported in 9–50% of as veno-occlusive disease, infection or drug patients who receive allogeneic hematopoietic toxicity. A liver biopsy is rarely performed for stem-cell transplants from a human leukocyte diagnostic purposes, as biopsies from skin or antigen (HLA)-identical sibling. In acute GVHD, gastrointestinal tract can be easily obtained with involvement of the gastrointestinal tract is less risk and a high diagnostic yield. characterized by voluminous watery diarrhea and abdominal cramping (Box 1). The diarrhea is RADIATION PROCTITIS secretory and can frequently become bloody.58 Patients receiving radiation therapy to the Patients can also present with upper gastro­ abdomen and pelvis for the treatment of gyneco­ intestinal tract symptoms (dyspepsia, food intoler­ logic, genitourinary, gastrointestinal and other ance, nausea, vomiting and anorexia) in the malignancies are at risk of developing acute and absence of lower gastrointestinal symptoms.59 chronic intestinal injury. In the rectum and distal Biopsies are helpful for making a diagnosis colon, acute radiation injury usually occurs of acute GVHD. The most consistent histo- within 6 weeks of beginning therapy and is logic feature of acute GVHD is apoptotic cell characterized by diarrhea, rectal urgency, tenes- death,60 but this feature is not specific to this mus and, occasionally, . These entity, and is also present in other conditions. symptoms usually resolve within 6 months The area of the gastrointestinal tract that should without the need for therapy.70 be targeted for endoscopic biopsies for the Chronic radiation proctitis or coloproctitis diagnosis of acute GVHD is a topic of debate. has a delayed onset, occurring on average a year Early publications suggest that rectal biopsies or later after exposure to radiation. This type of provide the highest diagnostic yield,61 while chronic injury is caused by obliterative endarter­ other studies have found that biopsies of the itis and chronic mucosal ischemia resulting in stomach62 and small bowel63,64 are most sensi- epithelial atrophy and fibrosis. The end result of tive regardless of whether the patient presents this process is stricture formation and bleeding with upper or lower gastrointestinal symptoms. within the colon and rectum. Patients with radia- Until data from prospective studies are avail- tion proctitis can present with diarrhea, bleeding, able, we recommend that biopsies be taken tenesmus, urgency, difficulties with from the stomach, and rectum when and less commonly .

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Box 2 Advantages and disadvantages of penetration, low cost compared with laser treatment options for radiation proctitis. treatment, and wide availability. The benefits enemas of APC for the treatment of radiation procti- 77–79 Some reports of improved symptoms (including tis have been shown in several case series. bleeding) without adverse effects Patients treated with APC have improvement in bleeding and anemia after a median of 2.9 treatment sessions.80 Lasers such as argon and Easy, safe and inexpensive Improvement in bleeding and anemia after Nd:YAG successfully control bleeding, but are approximately 2.9 endoscopic sessions expensive and not widely available. Bipolar electrocoagulation and heater probes are also Argon or Nd:YAG lasers effective for the treatment of radiation proctitis, Expensive but might cause more tissue injury compared Successful in controlling bleeding with APC or lasers. BICAP or heater probe Surgery should be considered in patients with Might cause greater tissue injury intractable symptoms such as strictures, pain or Surgery bleeding.81 In summary, the selection of treat- Considered for intractable symptoms such as ment for radiation proctitis should be based on strictures, pain or bleeding the type and severity of symptoms as well as Other (hyperbaric oxygen, short-chain fatty acid local expertise. enemas, rectal instillation of ) Some reports of improved symptoms DRUG HEPATOTOXICITY Abbreviations: BICAP, bipolar electrocoagulation; Nd:YAG, Patients undergoing chemotherapy require neodymium-doped yttrium aluminium garnet. careful assessment of liver function both before and during therapy. If liver function test results are abnormal, the etiology must be defined promptly and as clearly as possible. In addition The diagnosis of radiation proctitis is made to drug reactions, there are multiple potential by colonoscopy or sigmoidoscopy. Endoscopic causes of abnormal liver function test results in findings include mucosal edema, erythema, fri- patients undergoing chemotherapy, including ability and the presence of . In tumor progression, infection or the presence of severe cases, mucosal ulcerations and strictures coexisting hepatic disease. can be observed.71 Treatment for radiation proctitis should focus on the pattern of symptoms (Box 2). Some Patients with pre-existing can patients will present mostly with pain, diarrhea be more susceptible to drug-induced hepato­ and tenesmus and others exclusively with bleed- toxicity. Chemotherapy (including the use of ing. Sucralfate, administered orally or topically, monoclonal antibodies) can lead to reactiva- has been reported to improve symptoms (includ- tion of HBV and its associated disease.82–84 ing bleeding) without causing considerable Risk factors for HBV reactivation include HBV adverse events;72,73 however, studies investigating surface antigen and HBV envelope antigen sero- the efficacy of this drug have largely been uncon- positivity, detectable HBV DNA before chemo- trolled. Other treatments that have shown some therapy, male sex, diagnosis of lymphoma or benefit in small clinical trials include hyperbaric breast cancer, and use of steroids.82,85,86 oxygen,74 short-chain fatty acid enemas,75 and Prophylactic treatment with lamivudine seems rectal instillation of formaldehyde.76 to be beneficial in preventing HBV reactivation, Various thermal endoscopic therapies have also or reducing the severity of HBV-related disease in been used successfully to treat bleeding associ­ patients undergoing cytotoxic chemotherapy.87 ated with radiation proctitis, including argon Newer agents for treatment of are plasma coagulation (APC), argon and Nd:YAG available, but there are currently no studies con- (neodymium-doped yttrium aluminium garnet) cerning their use for prophylaxis in the setting lasers, bipolar electrocoagulation and heater of cancer chemotherapy or stem-cell trans­ probes. APC uses energy transmitted to tissue plantation. For short-term prophylaxis (less than by ionized argon gas and has gained popularity 6 months), lamivudine is a reasonable choice because of ease of application, safe depth of for treatment because the risk of developing

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lamivudine resistance during this time frame is other consistent with sclerosing cholangitis.93–95 extremely low. If, however, therapy is required 6‑MP is often used as a maintenance therapy for longer than 6 months, the use of either ade- in acute lymphoblastic leukemia, and two pat- fovir dipivoxil or entecavir instead of lamivudine terns of toxicity associated with its use have is recommended.71 been reported—hepatocellular injury and chole­ The relationship between chemotherapy and stasis.96 Hepatotoxicity caused by 6-MP occurs HCV reactivation is less clear than for HBV infec- more commonly when a daily dose of 2 mg/kg tion. It seems that the presence of HCV infection is exceeded. Azathioprine is a nitroimidazole increases the risk of having abnormal liver func- derivative of 6-MP. Toxicity with azathioprine is tion test results;88 however, severe flares of clinical less common and less dose-dependent than with hepatitis are extremely rare. 6-MP. Three different patterns of toxicity associ- ated with azathioprine have been described—a Idiosyncratic hepatotoxicities hypersensitivity reaction, an idiosyncratic Most hepatotoxic drug reactions are idio­ cholestatic reaction, and endothelial cell injury syncratic and are due to either hypersensitivity with development of elevated portal pressures, mechanisms or host metabolic idiosyncrasy.89 veno-occlusive disease and .97 High-dose methotrexate therapy has been Alkylating agents associated with reversible elevations in the levels Alkylating agents are uncommonly associated of aminotransferasess.98 It is interesting to note with hepatotoxicity. With the exception of cyclo- that patients taking long-term, low-dose metho­ phosphamide and ifosfamide, patients receiv- trexate therapy for psoriasis or rheumatoid ing alkylating agents generally do not require a arthritis are at risk of developing hepatic fibrosis dose reduction because of hepatotoxic adverse and ; however, the risk is low in patients effects. Cyclophosphamide is infrequently who receive less than 1.5 g of methotrexate as a hepatotoxic and its effect is probably due to an cumulative dose.99 idiosyncratic reaction. On rare occasions, diffuse hepatocellular destruction and massive hepatic Antitumor antibiotics necrosis associated with cyclophosphamide use The antitumor antibiotics include doxo­ have been described.90 Other alkylating agents rubicin hydrochloride and daunorubicin. (including melphalan, chlorambucil, nitrogen Doxorubicin hydrochloride can cause hepato­ mustards and busulfan) are not dependent cellular injury and steatosis, and dose reduc- upon the liver for their metabolism and are not tion has been recommended in patients with frequently associated with hepatotoxicity. cholestasis to avoid further toxicity.100 Similar guidelines are recommended for daunorubicin. Antimetabolites The antimetabolites commonly seen in clinical Neoadjuvant regimens use include cytarabine, 5-FU, 6-mercaptopurine Combinations of 5-FU and oxaliplatin or irino­ (6-MP), azathioprine, 6-tioguanine and metho- tecan hydrochloride are used as neoadjuvant trexate. Hepatic metabolism has an important therapy in patients with before role in the processing of these drugs, and dose resection of liver metastases. These neoadjuvant reductions are usually necessary in patients who regimens have been associated with steatosis, develop liver dysfunction. hepatic vascular injury and nodular regenerative Cytarabine is used for the treatment of acute hyperplasia.101–104 Veno-occlusive disease has myelogenous leukemia, and on rare occasions been seen with dacarbazine,105 6-MP,106 azathio­ has been associated with cholestasis, which prine,107,108 cyclophosphamide,109 busul- seems to be reversible.91 Only rare reports fan,110 and following treatment with ABVD of hepatotoxicity have been noted with use of (doxorubicin, bleomycin, vinblastine sulphate, intravenous 5-FU; however, hepatotoxicity can dacarbazine) for Hodgkin’s disease.111 be more common when 5-FU is administered in combination with ascaricides.92 Intra-arterial OTHER COMPLICATIONS administration of the 5-FU metabolite floxuri­ Nausea and vomiting dine (fluorodeoxyuridine [FUdR]) has been Nausea and vomiting frequently occur after associated with two types of toxicity—one administration of chemotherapeutic agents. The suggestive of hepatocellular injury, and the likelihood of developing nausea and vomiting

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Table 2 Other gastrointestinal complications associated with oncologic therapy. Complication Common causes Treatment

Nausea and vomiting Chemotherapy Antiemetic agents (5-HT3 receptor antagonists, NK-1-receptor antagonists, ), metaclopramide hydrochloride, butyrophenones, phenothiazines, cannabinoids, olanzapine Gastrointestinal perforation, Bevacizumab (monoclonal antibody Surgery for perforation of fistula fistula formation, arterial against VEGF) formation. Usually supportive care thrombosis and bleeding for bleeding Acute pancreatitis Causes unrelated to cancer Supportive: NPO, bowel rest, (, alcohol) and cancer-related intravenous fluids or TPN if (metronidazole, sulfonamides, tetracycline, needed, nasogastric tube suction furosemide, thiazides, estrogen, tamoxifen if needed and chemotherapy agents) Oral mucositis or ulceration Radiation, chemotherapy for solid Palifermin (patients with of the mucosal lining of the malignancies and patients undergoing hematologic malignancies) oropharynx hematopoietic stem-cell transplantation

Abbreviations: 5-HT3, 5-hydroxytryptamine-3; NK-1, neurokinin-1; NPO, nil per os; TPN, total parenteral nutrition; VEGF, vascular endothelial growth factor.

following chemotherapy depends on several Gastrointestinal perforation, fistula factors including the chemotherapy dose and the formation, arterial thrombosis and bleeding intrinsic emetogenicity of a given agent.112 Gastrointestinal perforation, fistula formation, The emetogenic potential of intravenously arterial thrombosis and bleeding have been administered antineoplastic agents can be reported with bevacizumab, a monoclonal anti- assigned to five levels, ranging from minimal body against VEGF (Table 2).113 Intestinal perfora­ or less than 10% risk (e.g. bevacizumab) to a tion has been reported in 1–2% of patients treated high or greater than 90% risk (e.g. cisplatin).105 with bevacizumab for metastatic colorectal Emesis can be acute (i.e. occurring within cancer.114,115 Risk factors associated with perfora­ the first 24 h of receiving chemotherapy) tion include an intact primary tumor, prior or delayed. irradiation, acute , intra-abdominal Various antiemetic agents are now available for abscess and gastrointestinal obstruction.116 the prevention and treatment of chemotherapy- induced nausea and vomiting (Table 2). These Acute pancreatitis include agents with a high therapeutic index Acute pancreatitis in patients with cancer or in such as 5-hydroxytryptamine-3 (5-HT3) recep- those who have undergone hematopoietic stem- tor antagonists (e.g. ondansetron, granisetron, cell transplantation can be caused by conditions dolasetron, tropisetron, palonosetron), neuro- present in the general population, including kinin-1-receptor antagonists (e.g. aprepitant) and alcohol. However, other etiolo- and corticosteroids (usually used in combina­ gies should be taken into consideration when tion with other agents). Agents with a low managing cancer patients who have acute therapeutic index are also used, such as meta- pancreatitis, including their medications and clopramide hydrochloride, butyrophenones, chemotherapeutic agents (Table 2). phenothiazines, cannabinoids and olanzapine. Drug-induced pancreatitis has no distin- The preferred agent and regimen depends on the guishing clinical features, and therefore taking a emetogenic level of a given chemotherapeutic careful drug history and excluding other etiolo- drug. For drugs with a low emetogenic risk, gies are essential to make a diagnosis. Some of the antiemetics are given only before chemotherapy, most common drugs known to cause acute pan- while antiemetics are provided before and creatitis include metronidazole, sulfonamides, after chemotherapy for those chemotherapy tetracycline, furosemide, thiazides, estrogen and drugs with a high emetogenic risk (levels 3 tamoxifen.117,118 The last two drugs might act or higher). via the induction of hypertriglyceridemia.119,120

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During the course of chemotherapy, pancreatitis The gastroenterologist has an important role has been reported with the use of azathioprine,121 in managing the gastrointestinal complications ifosfamide,122 prednisone,123 cytosine arabino- associated with various cancer treatments. It is, side,124 and various regimens of combination therefore, of importance that gastroenterolo- chemotherapy including vinca alkaloids, metho­ gists are aware of the adverse effects of oncologic trexate, mitomycin, 5-FU, cyclophosphamide, therapies and maintain communication with cisplatin and bleomycin. the treating oncologist so that the cancer and gastrointestinal adverse effects can be managed Oral mucositis or ulceration as effectively as possible. of the oropharynx Oral mucositis or painful ulceration of the KEY POINTS mucosal lining of the oropharynx occurs fre- ■ Gastrointestinal complications of oncologic quently in individuals undergoing radiation therapy are common and can affect all organs and chemotherapy for solid malignancies, and of the gastrointestinal tract; they are often life-threatening has been reported in up to 98% of individuals undergoing hematopoietic stem-cell trans­ ■ Treatment of gastrointestinal complications plantation (Table 2).125 Palifermin, a recombi­ of oncologic therapy should be individualized nant human keratinocyte growth factor to take into account the patient’s status and decreases the incidence and duration of muco- disease pathophysiology sitis in patients with hematologic malignancies ■ Gastrointestinal complications of oncologic who are receiving chemotherapy and requiring therapy are often multifactorial, involving direct stem-cell transplantation support, and has been toxicity and secondary events resulting from approved by the FDA for this indication. Results the immunosuppressive properties of given from phase I and II trials investigating the use agents of palfermin in patients receiving chemotherapy ■ Gastrointestinal complications of therapy must for solid tumors are also encouraging.125 be differentiated from of underlying disease

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