 |
Gastrointestinal complications are frequently encountered in patients undergoing cancer therepy, whether or not the tumor originated in the alimentary tract. Proper diagnosis and treatment of these conditions is a critical part of the multidisciplinary care of these patients. The increasing practice of hematopoietic cell transplantation has resulted in the development of gastrointesinal and hepatic complications that are unique to this treatment.
The majority of patients with esophageal cancer are not treatable for cure, due to an advanced tumor stage at diagnosis.1 Palliative treatment is mainly directed at relieving dysphagia, a frequent cause of patient distress and malnutrition.
| Mechanical factors, intraluminal |
| Peptic stricture |
| Esophageal cancer |
| Benign tumors |
| Lower esophageal ring (Schatzki’s ring) |
| Foreign bodies |
| Mechanical factors, extraluminal |
| Mediastinal abnormalities |
| Postradiation |
| Neuromuscular (motility disturbances) |
| Laser | Stent | PDT | |
|---|---|---|---|
| Tracheoesophageal fistula | No | Yes | No |
| Exophytic tumor | Yes | Yes | Yes |
| Infiltrative (nonexophytic) | No | Yes | Maybe |
| Cervical esophagus | Maybe | No | Yes |
| Gastroesophageal junction | Maybe | Maybe | Yes |
| Postradiation occurrence | Maybe | Maybe | Yes |
PDT = photodynamic therapy.
Modified from Rahmani EY, Rex DK. In: Yamada T, Alpers D, Laine L, Owyang C, Powell D, editors. Textbook of Gastroenterology. Philadelphia: Lippincott, Williams & Wilkins; 1999. p. 2889.
Peroral esophageal dilation can be performed safely and efficiently with successful initial results in up to 90% of patients.1,3,4 The procedure can be done using a variety of dilators; however, we prefer to use the Savary-Guilliard dilating system because it provides a gradual dilation with the added safety of a guidewire that can be used under fluoroscopic guidance. However, the procedure provides only a short interval of relief, so that frequent repeated dilation is the rule as often as every 11 days.3 Although dilation alone is a temporizing maneuver, it can facilitate additional endoscopic therapies.
The word laser is an acronym for “light amplification by the stimulated emission of radiation.” The most common type of laser energy used for tumor ablation is that produced by the neodymium:yttrium-aluminum-garnet crystal, or Nd:YAG. This laser has a greater depth of destruction and hemostatic properties than argon laser energy.5 Since the first report of its usefulness in patients with esophageal carcinoma, there have been numerous reports confirming the value of this therapeutic modality.5–10
Laser therapy results in symptomatic improvement in up to 97% of patients, with a reported complication rate ranging from 0 to 26%.5–10 Potential complications of laser therapy include hemorrhage, perforation, tracheoesophageal fistula, and bacteremia.10–12 In two recent series, complications occurred in less than 10% of patients.12 Treatment can be accomplished by using either the prograde approach (photocoagulation beginning at the proximal aspect of obstruction) or the retrograde approach (the esophagus is first dilated so that treatment can be given from the distal to proximal end). The latter approach appears to be preferable because it allows more rapid treatment without increased complications. There are few comparative studies of endoscopic laser therapy versus other endoscopic palliative treatments. In one study, both methods were successful (100% with laser versus 95% with polyvinyl stent6; however, the morbidity and mortality were higher for stent placement. Photodynamic therapy (PDT) follows the administration of a light-sensitive drug and is a newer treatment modality that is being actively studied for esophageal cancer treatment and for palliation of malignant dysphagia. In a study by Lightdale and colleagues,13 PDT was found to be a safe and effective therapy although it was equivalent to laser therapy for relief of malignant dysphagia.
Peroral insertion of an esophageal prosthesis is another useful treatment modality for the palliative management of esophageal cancer.2,14 Plastic or stainless steel re-inforced endoprostheses have been available for two decades. However, their insertion has been associated with a high rate of complications, including perforation, and has frequently provided suboptimal palliation of dysphagia.6,15–17 Self-expanding metallic esophageal stents have evolved as the primary treatment for malignant dysphagia.2,14,18 Advantages to these stents include relative ease of insertion, greater internal diameter, and low risk of perforation.19 These stents have been shown to be highly effective for the relief of dysphagia. However, these stents are costly, and problems exist, including tumor ingrowth and overgrowth, stent compression, mucosal erosion, stent migration, maldeployment, and inadequate expansion.18 Given the rapid pace at which stent technology is evolving, further improvements are expected and may surmount some of these problems. Esophagorespiratory fistulas are an indication for placement of an esophageal prosthesis.2,4,18,20 Polyurethane-covered self-expanding metallic stents have been shown to be highly effective therapy for such fistulae.20
The establishment of luminal patency cannot always be equated with functional success, i.e., the ability to meet caloric requirements by oral intake. One study investigating this issue reported a 97% technical success rate with laser therapy versus a 70% functional success rate, with the pretreatment performance status being the best predictor of functional outcome.21 It is important to note that tumor-associated anorexia is often the major factor limiting caloric intake despite restoration of a patent esophageal lumen. Therefore, patients may benefit from placement of a percutaneous endoscopic gastrostomy (PEG) tube. The overall approach to these patients is first to establish luminal patency with dilation and then to attempt to maintain it with either an endoprosthesis, laser therapy, or radiation therapy. Tracheoesophageal fistulae should be managed with an endoprosthesis.20 External-beam radiation therapy can be effective and is noninvasive. However, an important disadvantage is that relief of dysphagia occurs over a period of 4 to 6 weeks.22 Other palliative modalities include chemoradiation, brachytherapy, and surgery.22
In addition to mucositis, esophageal injury and infection are frequently recognized in patients undergoing cancer treatment and in the immunocompromised host. Esophagitis can be caused by cytotoxic chemotherapy and irradiation as well as by viral, bacterial, and fungal organisms.23 Other causes include acid-peptic esophagitis, pill-induced injury, trauma caused by nasogastric tubes, and graft-versus-host disease (GVHD) in hematopoietic-cell-transplant recipients.23,24 In nontransplant patients, Candida albicans and herpes simplex virus are the most common pathogens, but bacterial organisms and other viruses including cytomegalovirus (CMV) are also responsible.23 In severely immunocompromised patients, infection with multiple organisms may co-exist, and these organisms can become invasive due to mucosal disruption. Other predisposing factors include corticosteroids, diabetes mellitus, and acquired immune deficiency states. In patients receiving bone marrow or stem cell transplants, prophylaxis with antifungal and antiviral drugs has substantially reduced the incidence of esophageal infections.25,26 When esophagitis is suspected, endoscopy is the preferred diagnostic procedure and allows the early administration of appropriate therapy. In addition to visual inspection, endoscopic brushings and biopsies can be obtained for microscopic examination, special stains, and culture.23 Double-contrast esophagography will reveal evidence of esophagitis in severe cases, but sensitivity and specificity are limited.
Many Candida species normally colonize the oropharynx and can become pathogenic and produce esophagitis in immunocompromised patients.23,25 Patients may be asymptomatic or may complain of odynophagia (painful swallowing) and/or dysphagia (difficulty swallowing). Oral thrush may be absent. Endoscopy reveals slightly raised, adherent whitish plaques or linear streaks with surrounding erythema.27 In more severe cases, these plaques may be confluent, and in thrombocytopenic patients, bleeding may occur. In granulocytopenic patients, exudative material is usually absent. In either setting, the diagnosis is made at endoscopy by the finding of yeast or hyphal forms on cytologic smears of exudative material from esophageal brushings; mucosal biopsy is frequently nondiagnostic. Drugs that suppress acid production (H2-blockers, proton pump inhibitors) contribute to fungal and bacterial colonization of the upper gastrointestinal tract that can predispose to infectious esophagitis.23 Fluconazole is an effective treatment of esophageal candidiasis in immunocompromised patients.23,25 Unlike ketoconazole, its absorption is not affected by increased gastric pH. Treatment-refractory patients, those with granulocytopenia, or those with suspected disseminated infection should be treated with amphotericin B. In nonimmunocompromised patients, oral nystatin or clotrimazole troches are often successfully used for initial therapy. In patients with acquired immunodeficiency syndrome (AIDS) and suspected esophageal candidiasis, empiric treatment with fluconazole is frequently performed.28
Viral infections of the esophagus are caused by herpes simplex virus (HSV), CMV, and (rarely) varicella-zoster virus (VZV).23,29 Symptoms include odynophagia, dysphagia, retrosternal chest pain, and nausea/vomiting. In transplant recipients, nausea and vomiting appear to be the most frequent presenting symptoms.28–30 A history of an oral herpetic lesion or the presence of vesicles on the lips or buccal mucosa can be an important clue to the diagnosis of herpetic esophagitis. HSV produces esophageal ulcers that when viewed endoscopically can be discreet with erythematous borders or can coalesce into large areas of denuded mucosa.27,31 Mucosal cells from a biopsy sample taken at the edge of an ulcer or from a cytologic smear show intranuclear inclusions in otherwise normal epithelial cells, and multi-nucleated giant cells may also be observed.31 Using monoclonal antibodies to HSV, inclusions can be detected by immunohistochemistry.23,31 Culture for HSV becomes positive within days and can be helpful in diagnosis. Acyclovir is used for both prophylaxis and treatment. Either HSV type 1 or type 2 may afflict patients who are immunosuppressed. VZV can produce esophagitis in adults with herpes zoster, usually in the setting of disseminated infection.23,30 In some cases, esophageal VZV can be the source of disseminated VZV in the absence of skin involvement. In the immunocompromised host, VZV esophagitis causes vesicles and confluent ulcers and usually resolves spontaneously. On histologic examination of biopsy specimens or cytologic material, distinction from HSV requires immunohistochemistry or culture.
CMV esophageal infection occurs only in immunocompromised patients and is usually activated from a latent stage or acquired from blood product transfusions.23,32 CMV infects endothelial cells and fibroblasts but not epithelial cells as with HSV and VZV. CMV produces esophageal ulcerations that are often serpiginous and that can coalesce to form very large ulcers, particularly in the mid- and distal esophagus.27 Diagnosis requires endoscopy and biopsy of the center of the ulcer crater. Routine histology demonstrates intranuclear inclusions in fibroblasts and endothelial cells. Immunohistochemistry with anti-CMV antibodies is more sensitive than routine histology but less so than viral culture for establishing the diagnosis.33 In contrast to routine viral culture, the shell vial culture method provides a rapid (24-hr) result. Ganciclovir is the treatment of choice,34 and foscarnet is an effective alternative treatment.35 Human immunodeficiency virus (HIV) may be associated with esophageal ulceration, oral uclers, and a maculopapular skin rash that occurs at the time of HIV seroconversion.23,28 Persistent, deep esophageal ulcers may occur in chronically infected individuals and in those with AIDS.
Bacterial esophagitis occurs in the immunocompromised host, is usually polymicrobial, and derives from oral flora.30,36 This entity is underdiagnosed in severely granulocytopenic patients, given that bacteria are difficult to identify on routine histologic examination. In such patients, bacterial infection often co-exists with viral or fungal organisms that are more readily detected. Suppression of gastric acid production (by proton pump inhibitors) may predispose to bacterial and fungal esophagitis. The diagnosis is made by endoscopic biopsy, and in these specimens, clusters of bacteria are mixed with necrotic epithelial cells.36 Treatment consists of broad-spectum antimicrobial therapy.
Radiation esophagitis commonly occurs during treatment of intrathoracic malignancies, particularly lung and esophageal cancers. The frequency and severity of esophagitis increases with radiation dose and with the use of certain chemotherapeutic agents, including doxorubicin, bleomycin, cyclophosphamide, and cisplatin.23,37–39 Symptoms include odynophagia and dysphagia as well as retrosternal chest pain. At endoscopy, findings include erythema, edema, and friability of the esophageal mucosa, as well as ulceration with eventual stricture formation.27 Strictures result from submucosal fibrosis and degenerative changes involving blood vessels.40 Symptomatic strictures can be managed with esophageal dilation. Treatment includes relief of odynophagia with viscous lidocaine during the acute phase and use of H2-blockers or proton pump inhibitors to prevent further acid-related injury.
Pill-induced esophagitis can occur in patients taking medications at bedtime or in the recumbent position and with too little liquid.23 Medications associated with esophageal injury include potassium chloride, tetracycline, and phenytoin. Acid peptic injury to the esophagus can result in patients who are undergoing cancer treatment.23 Predisposing factors include delayed gastric emptying, esophageal dysmotility, impaired acid clearance, and a history of gastroesophageal reflux disease.
Esophageal involvement by GVHD is uncommon in patients with chronic GVHD.24,41 Affected patients have desquamation of the esophageal mucosa and may also develop submucosal fibrosis and stricture formation.42 Patients usually complain of dysphagia but may also have retrosternal discomfort and reflux-related symptoms due to reduced esophageal peristalsis. Salivary gland destruction secondary to GVHD also impairs swallowing and reduces acid neutralization and clearance. Treatment of chronic GVHD at its early stages may prevent esophageal involvement.
The diagnosis and management of acute gastrointestinal bleeding is well covered in standard textbooks of gastroenterology. The goal of this section will be to focus on aspects of intestinal mucosal injury and infection that can lead to significant bleeding in cancer patients undergoing therapy. In patients receiving chemotherapy, retching and nausea/vomiting are better controlled with antiemetics, including serotonin antagonists.43 However, emetogenic injury to the gastric mucosa and the gastroesophageal junction (Mallory-Weiss tear) commonly occur and produce upper gastrointestinal bleeding.44 These injuries can produce very significant bleeding in the setting of thrombocytopenia. The etiology of upper gastrointestinal bleeding in patients with cancer is commonly due to benign causes. In a series that included 122 cancer patients with upper gastrointestinal bleeding, 95 (78%) had gastritis, peptic ulcer disease, or severe esophagitis as the cause of their hemorrhage.45 The development of thrombocytopenia and/or coagulopathy can unmask focal pathology and lead to gastrointestinal bleeding. Patients with cancer and those undergoing cancer treatment are at risk for stress-related mucosal injury.
Stress-related mucosal injury is a common problem frequently seen in critically ill patients, including those with cancer. Many terms have been associated with this entity, including stress-related mucosal damage, stress ulceration, erosive gastritis, and stress ulcer syndrome. The reported incidence of bleeding in patients at risk for stress-related mucosal damage varies according to the diagnostic criteria applied. Painless, occult or overt upper gastrointestinal bleeding can develop in up to 20% of patients in an intensive care unit (ICU) setting.46 Significant hemorrhage is reported to occur in approximately 6% of patients. The likelihood of significant bleeding from stress-related mucosal lesions depends upon risk factors such as thrombocytopenia, coagulopathy, sepsis, major surgical procedures, and the presence of organ failure.47 Use of nonsteroidal anti-inflammatory drugs (NSAIDs) is also a risk factor. Endoscopic findings include multiple superficial erosions or ulcers that arise most often in the gastric fundus. Most deaths are due to underlying illness; however, up to 30% of patients with clinically significant hemorrhage die as a direct result of bleeding.47 The pathophysiology of stress-related mucosal injury involves an imbalance between injurious and defensive mucosal factors, the latter of which are disrupted by acute physiologic stress. In addition, a low gastric luminal pH and reflux of acid and bile into the esophagus and stomach may serve as exacerbating factors; the role of Helicobacter pylori infection remains to be determined. While most patients do not have acid hypersecretion, it appears that acid is an essential permissive factor since reduction of gastric acidity with antacids, H2 receptor antagonists, and proton pump inhibitors can prevent these lesions.48
Primary tumors of the gastrointestinal tract and mucosal metastatic tumor or chloroma are causes of occult bleeding, but they can also produce acute hemorrhage. With intestinal primary cancers, bleeding often ceases spontaneously and with conservative therapy. Endoscopic therapy is frequently not helpful due to diffuse oozing from the tumor surface and, therefore, lack of a discreet focus amenable to electrocautery or other endoscopic modalities. Patients with hemodynamically significant bleeding can be referred for angiography with possible embolization, and in some cases, surgery is required.
In bone marrow transplant recipients, the frequency of gross intestinal bleeding occurs in fewer than 10% of patients within the first 100 days49 and has fallen significantly over the past decade. This drop is attributed to effective prophylaxis against viral and fungal infection and acute GVHD. Of note, acute GVHD with diffuse small intestinal ulceration is the most common cause of bleeding in these patients.49 In transplant patients, transfusion of platelets to achieve counts of 60,000/μL or above will generally control bleeding such that endoscopic control is often not needed.
Pre-existing ulcers may bleed profusely post-transplantation, particularly those lesions with an exposed submucosal vessel. Endoscopic therapies are generally unsuccessful in the thrombocytopenic patient but can be attempted if the platelet count is above 50,000/μL and stable. Otherwise, embolization or surgery are usually urgently needed. Ulcers of the esophagus, stomach, or duodenum in the post-transplantation patient may be caused by GVHD or CMV and HSV (esophagus) infection, particularly in patients not receiving antiviral prophylaxis,23 and can bleed profusely. Significant bleeding from the site of endoscopic biopsies of the duodenal mucosa may occur in patients with GVHD.44 Re-epithelialization occurs slowly in such patients, who are often thrombocytopenic. This complication can be avoided by obtaining gastric biopsies instead of duodenal biopsies and by maintaining platelet counts above 60,000/μL.
The goals of management include hemodynamic stabilization, establishment of an accurate diagnosis, and initiation of medical therapy with the objective of preventing further bleeding. Endoscopy is the preferred diagnostic procedure and should be performed in all patients with gross bleeding and in patients with ongoing occult blood loss. Over the past several years, advances in endoscopic treatment have included thermocoagulation, endoscopic injection of adrenaline or alcohol for active bleeding, and laser therapy.50 These treatment modalities have added much to our ability to control gastrointestinal bleeding by nonsurgical means. Treatment-related anemia also decreases reserves; therefore, gastrointestinal hemorrhage can be life-threatening in cancer patients.
Cook and colleagues48 reviewed 63 relevant randomized studies regarding stress ulcer prophylaxis in critically ill patients and concluded that there is strong evidence of reduced clinically important gastrointestinal bleeding with H2 antagonists versus no therapy. However, no evidence exists that prophylactic therapy decreases mortality rates. Fluid resuscitation and blood transfusion are important for re-establishing and maintaining hemodynamic stability. Attempts to correct coagulopathy with fresh frozen plasma is employed in patients with active bleeding. In thrombocytopenic patients, platelet transfusion is used to maintain the platelet count above above 60,000/μL and preferably above 100,00/μL. Intravenous H2 blockers are used, and in severely thrombocytopenic patients, we generally remove nasogastric tubes due to their ability to produce erosion and bleeding in such patients. Endoscopic therapies used to achieve hemostasis include bicap electrocoagulation, heater probe, and the argon plasma coagulator.50 Epinephrine injections are also employed for treatment of actively bleeding lesions.50 Other therapies include the use of intravenous vasopressin or somatostatin although these drugs have not shown benefit in patients with ulcer-related bleeding, in contrast bleeding esophageal varices.51 Other alternatives include surgical therapy or arteriography with embolization.
Clostridium difficile is the most common bacterial cause of infectious diarrhea in antibiotic-treated patients52 and in those undergoing cancer chemotherapy.53–55 Essentially any antibiotic can cause this syndrome, however, those drugs that are prescribed most frequently (i.e., cephalosporins followed by the penicillins) are most commonly implicated. Cancer patients receiving chemotherapy appear predisoposed to C. difficile–induced diarrhea even in the absence of antibiotics.53–55 In a study of such patients, methotrexate, doxorubicin, and cyclophosphamide were the drugs most frequently associated with C. difficile infection.55 It is speculated that anticancer-drug-mediated mucosal injury may produce the anaerobic environment conducive to C. difficile colonization.
Diarrhea is the key feature and is usually watery, voluminous, and without gross blood. Most patients have abdominal pain and tenderness, fever, and leukocytosis, although symptoms vary52,56 and generally begin after 5 to 10 days of antibiotic therapy; however, they may occur as late as 3 to 4 weeks after discontinuation of therapy.57 Diarrheal volumes in patients infected with C. difficile are generally lower than those found in those with acute GVHD. Diarrheal disease due to C. difficile is toxin mediated.58,59 Diagnosis requires detection of C. difficile toxin in the diarrheal fluid or by culture.59 In patients found to have pseudomembranes of the colorectal mucosa at endoscopy, nearly all will have positive C. difficile toxin stool assays. Examination of the stool frequently reveals leukocytes. The left colon including the rectum is most commonly involved, but a predominantly right-sided colitis is also possible. Therefore, a normal flexible sigmoidoscopic examination does not exclude the infection but will detect approximately 80% of cases. Endoscopic evaluation reveals a spectrum from mild colitis to classic pseudomembranous colitis.56 Of importance, typical pseudomembranes on the colorectal mucosa may be absent in granulocytopenic patients. Endoscopic findings include an erythematous and edematous colorectal mucosa that is occasionally friable. Pseudomembranes appear as distinct, adherent raised yellow-white plaques that are usually 2 to 5 mm in diameter but can be confluent, covering several centimeters of colonic mucosa.27,56 Protein-losing enteropathy is an infrequent complication.60 Histologically, biopsy specimens demonstrate a pseudomembrane with inflammation of the underlying mucosa; ulcerations of the mucosa and involvement of the serosa rarely occur.56,61 Pseudomembranes are composed of polymorphonuclear leukocytes, chronic inflammatory cells, epithelial debris, and fibrin.
C. difficile is a large, spore-forming, gram-positive anaerobic rod that is rarely detected in the feces of healthy adults who have not received antimicrobial therapy.59,62 Isolation of the organism does not in itself imply active disease. Rather, in the proper clinical context, identification of toxin in stool is consistent with infection and remains the best diagnostic test for pseudomembranous colitis.52,56 After the organism is acquired, a change in intestinal flora due to antibiotics appears to permit C. difficile to overpopulate the intestine.59 Infection is noninvasive, and blood cultures are therefore negative. At least three potential virulence factors have been described: enterotoxin (toxin A), a cytotoxin (toxin B), and a distinct motility-altering factor.58 Toxin A mediates alterations in fluid secretion and enhances inflammation. Toxin B is more active than A in causing damage and exfoliation of intestinal epithelial cells. Laboratory diagnosis depends on examination of the feces for the presence of C. difficile toxin A. The toxin can be detected by observing its characteristic cytopathic effect in tissue culture.59 A rapid latex agglutination test for the detection of toxin A is available. Since immunospecific cross-reactions have been documented with certain other organisms, the latex test should be used only as a screening procedure.63 Positive latex tests should be confirmed by another assay when clinically indicated.
The treatment of antibiotic-associated pseudomembranous colitis requires discontinuation of the implicated antibiotic.52 Many patients improve spontaneously with only this measure; however, specific therapy shortens the duration of symptoms. The most widely used agent is oral vancomycin, which like metronidazole, is poorly absorbed and reaches high concentrations in the stool.52,56 Both oral vancomycin and metronidazole are effective treatments of pseudomembranous colitis, and a comparison of these agents in a randomized trial demonstrated equal efficacy and relapse rates of 8 to 9%, respectively.64 Metronidazole is much more economical than vancomycin and is therefore recommended for initial therapy.52,55 The usual initial dosage is 250 mg q.i.d., but 500 mg t.i.d. is also appropriate. Vancomycin is often reserved for patients who fail to respond to metronidazole therapy. A randomized trial found that vancomycin at 125 mg orally four times daily for an average of 10 days was as active as the 500-mg dose given four times daily.65 Relapse of symptoms and a repeat positive toxin assay is not uncommon after responding to and completing initial therapy. Most relapsing patients will respond to a second course of treatment, but some patients suffer multiple relapses.52,53 Some relapsing patients have been shown to acquire a different strain of C. difficile, and these patients will respond to a second course of the same antibiotic. Alternately, one can use vancomycin if metronidazole was used initially, and vice versa. Cholestyramine is an anion exchange resin that binds to the enterotoxin of C. difficile (aborts its cytotoxic activity in vitro), and that has been used with success in refractory cases.56 Cholestyramine also binds vancomycin; therefore, these agents should not be used in combination. In the rare patient with a severe complication such as toxic megacolon or perforation, surgical management may be required.52,66
Typhlitis refers to a clinical syndrome of fever and right-lower-quadrant tenderness in a neutropenic patient after cytotoxic chemotherapy. Typhlitis (from the Greek word typhlon, meaning cecum) is also referred to as neutropenic colitis,67,68 necrotizing colitis,69 ileocecal syndrome, or cecitis.70 This syndrome is seen in patients treated with cytotoxic drugs usually for hematologic malignancies, especially acute myelogenous leukemia and acute lymphoblastic leukemia.71 Typhlitis appears to be more common among children than adults.70,72–75 Typhlitis may also complicate the treatment of patients with solid tumors76 and granulocytopenia from other causes.77,78 Although the cecum is most commonly affected, other potential areas of involvement include the ileum and ascending colon.69,70,75,79 In our experience, patients with typhlitis have been granulocytopenic for 1 or more weeks before the onset of symptoms. Typhlitis is a consequence of overgrowth of clostridia, particularly Clostridium septicum, in granulocytopenic patients.80 The process appears to begin with mucosal disruption, leading to secondary intramural infection and subsequent edema, induration, and wall thickening.69,79,81 Chemotherapeutic agents may themselves alter mucosal integrity.82 To date, a predictor of this syndrome has not been identified, in that chemotherapy, neutropenia, fever, and antibiotic use are found with equal frequency in patients with and without typhlitis.69,79,83
Typhlitis should be suspected when a neutropenic patient presents with fever and abdominal pain, particularly in the right lower quadrant, with or without rebound tenderness. Associated diarrhea, often bloody, is common. Abdominal distention and nausea/vomiting are also common symptoms.69,74,79 Given that the clinical presentation can be subtle and there are no pathognomonic clinical findings, one must consider other entities in the differential diagnosis, such as pseudomembranous colitis, colonic pseudo-obstruction, acute appendicitis, ischemic colitis, inflammatory bowel disease, and infectious colitis. Imaging studies can be useful in supporting a diagnosis of typhlitis. Computed tomography (CT) and ultrasonography can demonstrate bowel wall thickening and exclude other intra-abdominal processes. CT and magnetic resonance imaging (MRI) are more sensitive for diagnosis than are other imaging modalities, and they are noninvasive.81,84 Plain radiography is nonspecific but may show any of the following features: a relative paucity of bowel gas in the right lower quadrant, with a slight distention of surrounding small bowel; a soft-tissue density secondary to an atonic, fluid-filled right colon that may be dilated and may exhibit thumbprinting of the mucosa; or small bowel obstruction.75,85 Findings at colonoscopy include mucosal erythema, edema, friability, and ulcerations. In some cases, a nodular tumorlike mass is seen.86 Colonoscopy should be done cautiously to minimize the risk of perforation. Alternatively, flexible sigmoidoscopy can be performed to exclude pseudomembranous colitis, inflammatory bowel disease, and infectious colitis. Barium enema, if it is to be performed, should also be done with caution, and findings include cecal distortion with edema and effacement of the mucosa, rigidity, loss of haustral markings, and thumbprinting.70,87 On pathologic examination, the bowel is dilated and edematous, and the mucosa is frequently hemorrhagic and may contain multiple ulcerations.79 Transmural involvement may be present, and there is usually a sparse inflammatory infiltrate, edema (so-called phlegmonous colitis), intramural hemorrhage, necrosis, and evidence of either bacterial or fungal infection. Leukemic infiltration is not routinely found.83
| Medical Management | Surgical Management | |||||
|---|---|---|---|---|---|---|
| Reference | Year | No. of Patients | n | Death | n | Death |
| Varki et al.71 | 1979 | 1 | — | — | 1 | 0 |
| Dworkin et al. 83 | 1981 | 1 | 1 | 0 | — | — |
| Alt et al.67 | 1985 | 2 | — | — | 2 | — |
| Sherman and Woolley70 | 1973 | 11 | 8 | 8 | 3 | 1 |
| Moir et al. | 1986 | 16 | 10 | 5 | 6 | 2 |
| Mower et al. | 1986 | 13 | 5 | 5 | 8 | 0 |
| Shamberger et al.74 | 1986 | 25 | 21 | 1 | 6 | 1 |
| Starnes et al. | 1986 | 5 | 4 | 0 | 1 | 0 |
| Villar et al. | 1987 | 19 | 15 | 14 | 4 | 1 |
| Skibber et al. | 1987 | 16 | 3 | 3 | 13 | 1 |
| O’Brien et al. | 1987 | 7 | 7 | 0 | — | — |
| Wade et al. | 1992 | 22 | 16 | 11 | 6 | 3 |
| Total | 138 | 90 | 47 | 50 | 9 | |
Modified from Williams and Scott.68
Vincristine treatment is associated with adynamic ileus and has been implicated in some cases of cecal perforation.88 Although the etiology of vincristine-induced ileus is not known, improvement has been reported with the use of metoclopramide.89 Cisapride may also be beneficial in that this agent improves motility throughout the intestinal tract whereas metachlopramide’s effect is limited to the upper gastrointestinal (GI) tract. Patients with vincristine-induced ileus often have obstipation, and aggressive use of cathartics may be needed.
Acute colonic pseudo-obstruction was first described in 1948 by Ogilvie, when he reported two patients with nonobstructive abdominal distention who ultimately were found to have metastases invading the subdiaphragm sympathetic plexus.90 This condition is characterized by massive dilation of the colon without apparent mechanical obstruction.91
The pathogenesis of acute colonic pseudo-obstruction is unknown. Autonomic imbalance has been suggested. The predilection toward massive cecal distention may be related to a combination of poor intestinal motility, prolonged recumbency in the supine position, or a mobile cecum on a loose mesentery.92
Patients with acute colonic pseudo-obstruction are generally quite ill and may have any of a wide range of underlying medical or surgical problems, including malignancy and cancer treatment. Typically, patients present with moderate to marked abdominal distention. Symptoms may include nausea, vomiting, abdominal pain, constipation, diarrhea, and occasionally, fever.93 Physical examination reveals abdominal distention, and bowel sounds may be diminished, normal, or hyperactive. Mild abdominal tenderness may be present. The presence of peritoneal signs, however, suggests complications of ischemia or perforation.94 Mild leukocytosis and electrolyte imbalances (particularly hypokalemia) are not uncommon.
Plain abdominal radiography provides the most useful diagnostic information. All patients have marked dilatation of the colon (usually most severe in the cecum and transverse colon), increased cecal diameter, and the absence of air-fluid levels on an upright film. Absence of mechanical colonic obstruction is demonstrated by using views and other maneuvers to allow gas to move freely into the left colon and rectum. The differential diagnosis includes true colonic obstruction, ischemic colitis, and toxic megacolon. Sigmoidoscopy, colonoscopy, or barium contrast studies can help to rule out distal mechanical obstruction but must be done with caution due to the risk of cecal perforation. A gastrograffin enema should be performed if colonic perforation is suspected.
Acute colonic pseudo-obstruction is a transient reversible condition whose most feared complication is perforation of the cecum or right colon. The cecum is most vulnerable to perforation due to the law of Laplace, which states that the tension on the bowel wall is directly proportional to the radius of the hollow viscus. Although perforation is relatively unusual, the goal of treatment is to avoid its occurence. Neither the natural history nor the specific factors that may predict perforation are known with certainty. However, the variables most often cited are the maximal cecal diameter and the duration of colonic dilation. Various authors have recommended some form of intervention when the cecum reaches a diameter ranging from 9 to 14 cm.95,96 Others have considered the duration of cecal enlargement to be more important. In one series, 75% of patients who suffered a perforation had documented cecal dilation for at least 5 days.92 Therapeutic modalities include conservative measures, colonoscopic decompression, and surgery.
Conservative measures include correction of fluid and electrolyte abnormalities; intravenous fluids; restriction of oral intake; nasogastric suction to minimize swallowing; discontiuation or at least a decrease of any medications that may interfere with bowel motility (especially narcotics); and serial physical examination and abdominal radiography to assess improvement or worsening or development of perforation.93,97 Frequent turning of the patient to the prone position allows redistribution of colonic gas into the descending colon and easier evacuation. In one study of 25 cancer patients with acute colonic pseudo-obstruction, 23 of 24 patients treated conservatively improved according to clinical and radiologic criteria in a mean of 3 days.97
This endoscopic procedure should be considered when conservative management is unsuccessful or when the cecal diameter is deemed to be dangerously dilated.98 The success rate is very high, and placement of an indwelling decompression tube (over a guidewire) is often performed. This decompression catheter may need to remain in place for longer-term benefit.
Surgical intervention is required when the above-mentioned therapeutic options fail or when there is evidence of colonic perforation.99 Tube cecostomy has been recommended for the patient with perforation.95 Perforations should be exteriorized, and adequate decompression should be assured; some patients may require colectomy.100
Diarrhea is a common complication of cytotoxic therapy that can result in fluid and electrolyte imbalance and compromise nutritional status. Cytotoxic agents target metabolically active tissues, including the small intestinal and colonic epithelium of the gastrointestinal tract.101 Mucosal damage by these agents produces net fluid secretion by the intestine and damage to intestinal villi with a loss of absorptive capacity.102 The net effect is a secretory diarrhea, although these patients often have a reduced capacity to handle an osmotic load, and thus, diarrhea is worsened by oral intake. Some anticancer drugs have a greater propensity than others to produce diarrhea; these include 5-fluorouracil (5-FU),103–105 cisplatin,106 and irinotecan.107–109 The incidence of diarrhea with 5-FU is increased by the addition of leucovorin.103,104 In a phase III study comparing different regimens for treatment of colorectal cancer, the frequency of severe diarrhea was highest in the group receiving weekly 5-FU plus high-dose leucovorin (25%) compared to those receiving 5-FU plus low-dose leucovorin (13%).110 When 5-FU alone was given for 5 consecutive days every 4 weeks, the frequency of severe diarrhea was 9%.110 The toxic effects of 5-FU have also been shown to depend upon age and sex, being more common in women than men and worse in women over age 70.105
The topoisomerase-I inhibitor irinotecan (CPT-11) can cause diarrhea by two separate mechanisms. A hyperacute diarrhea with abdominal cramping appears to be mediated by a cholingeric effect and can be effectively treated with atropine as well as loperamide.107,111 The delayed (more than 24 hours post infusion) type of diarrhea induced by this agent correlates with the peak plasma concentration of the metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).112 The exact mechanism of this type of diarrhea remains unknown. Irinotecan-induced diarrhea can be severe, and more than 18% of patients treated with this agent require hospitalization for management of diarrhea alone or in combination with other gastrointestinal symptoms.113 Early and aggressive antidiarrheal therapy with loperamide and/or diphenoxylate can significantly reduce the proportion of patients developing uncontrolled diarrhea and its complications of dehydration and electrolyte imbalance.107,114,115
Radiation therapy produces gastrointestinal mucosal injury that peaks 1 to 2 weeks after irradiation with subsequent resolution of symptoms. Worsening of diarrhea is seen with combined modality therapy, as with the neoadjuvant treatment of rectal cancer.116 When combined with radiation, continuous-infusion 5-FU produced a significant increase in the incidence and severity of diarrhea than was seen with an intravenous bolus of 5-FU.116
In patients undergoing bone marrow or stem cell transplantation, diarrhea may be secondary to the conditioning regimen or GVHD or due to infections related to immunosuppressive therapy. Diarrhea in the immediate post-transplantation period is generally due to injury to the intestinal mucosa caused by the conditioning regimen. This regimen includes total body irradiation (TBI) and/or a combination of chemotherapy agents. Regimens containing cytarabine and the combination of bulsulfan, melphalan, and thiotepa117–119 have been associated with more-severe and prolonged diarrhea. The severity of enteritis can vary and may reflect variability in metabolism and concentration of toxic metabolites.120,121 In general, diarrhea related to the conditioning regimens resolves by the third week after treatment. Histologically, this injury is characterized by crypt abnormalities, including nuclear atypia, mucosal flattening, and crypt cell degeneration and crypt obliteration due to apoptosis.122,123 Mucosal injury results in net fluid secretion by the intestine, i.e., secretory diarrhea, and resolves with mucosal restitution. After day 20, acute GVHD is the most common cause of diarrhea in these patients.119 Therefore, persistent diarrhea should raise the suspicion of acute GVHD and/or infectious etiologies, although the latter occur less frequently in this population. In patients with persistent diarrhea, colorectal mucosal biopsy can be performed to assess for mucosal regeneration and to evaluate for GVHD.122,123
GVHD is the most common cause of diarrhea in hematopoietic cell transplant recipients124 and is more frequent in recipients of allogeneic versus autologous transplants.119,125 In a prospective study of 296 consecutive patients undergoing bone marrow transplantation (BMT), 43% developed diarrhea after day 20 and during the first 10 months of follow-up. Of these cases, 48% were attributed to acute GVHD.124 Patients with GVHD-related diarrhea pass large volumes of watery fluid that often contains some mucoid material.126 GVHD-related diarrhea is secretory and occurs in the absence of oral intake, although such intake usually exacerbates the diarrhea. The suspicion of GVHD is supported by the presence of GVHD-associated skin and liver abnormalities, which when present, are nearly diagnostic of intestinal GVHD. GVHD as the cause of diarrhea is supported by stool studies negative for C. difficile toxin and enteric pathogens and by a falling serum albumin secondary to intestinal protein loss.124 Patients with intestinal GVHD usually complain of anorexia and crampy abdominal pain and may also have nausea/vomiting and fever. In more severe cases, patients can develop intestinal ileus or pseudo-obstruction. When the diagnosis is in question, endoscopic examination and biopsy are useful for definitive diagnosis and to exclude CMV enteritis. The latter is important in CMV seropositive patients who have not received prophylactic ganciclovir given that endoscopic biopsy will differentiate the two conditions.127
The yield from mucosal biopsy to establish the diagnosis of GVHD is higher from gastric specimens as opposed to duodenal or rectal specimens.124,128 However, a rectal biopsy is easier to perform using a flexible sigmoidoscope and is less costly than upper gastrointestinal biopsy. A recent report emphasizes the complementary nature of endoscopic and histologic examination and demonstrates that histologic findings in the upper gastrointestinal tract, unless severe, can underestimate the severity of GVHD elsewhere in the GI tract.123 In patients with significant nausea and/or vomiting, upper endoscopy with biopsy is the preferred diagnostic test. In mild GVHD, the intestinal mucosa may appear grossly normal or have a mild granular appearance. Moderate to severe GVHD is associated with granular, erythematous, and edematous mucosa, and in severe cases, mucosal ulceration or large areas of mucosal sloughing may be present.129–131 Patients with severe cases will often pass bloody stools, and this is worsened by concurrent thrombocytopenia. Abdominal x-rays and CT scans reveal edema of the intestinal wall.132,133 Although not specific for GVHD, these studies can in some cases reveal the extent of intestinal involvement. Barium studies of the small bowel reveal bowel wall thickening, with effacement of folds and excess luminal fluid.134
Mechanisms of diarrhea in GVHD include epithelial cell loss, impaired absorption, and increased vascular permeability due to cytokine release.119,135 The histologic hallmark of GVHD is apoptosis of intestinal crypt epithelial cells.130,136 This mechanism of epithelial cell loss is mediated by cytotoxic T lymphocytes135 and is detected by microscopic examination of biopsy specimens.122,137,138 Acute GVHD is treated with immunosuppressive drugs, which if effective, can dramatically reduce stool volume and accompanying gastrointestinal symptoms. Evidence indicates that approximately one-half of patients with acute GVHD respond to initial therapy.125 The somatostatin analogue octreotide can also reduce stool volume in patients with mild to moderate GVHD.139,140 The antidiarrheal effects of octreotide are due to inhibition of fluid secretion, enhanced electrolyte absorption, and decreased motility. Octreotide, however, was shown to be ineffective in steroid-resistant cases of intestinal GVHD.141 Opioids can also be used to treat GVHD-related diarrhea, and the patient should be observed carefully for abdominal distension.
Infectious diarrhea is relatively uncommon in the post-transplantation period. In a prospective study of patients following BMT, 43% of 296 patients developed diarrhea, with only 13% having a documented enteric infection.124 Pathogens identified in this study included astrovirus, adenovirus, rotavirus, and CMV; bacteria included C. difficile and Aeromonas species. As a cause of diarrhea, viral infection was more common than bacterial infection. The incidence of CMV infection has decreased markedly with the use of ganciclovir prophylaxis. CMV frequently produces diarrhea and bleeding due to mucosal ulceration.129,142 The presence of discreet or large serpiginous ulcers is highly suggestive of CMV infection.143,144 Diagnosis of CMV is made by endoscopic biopsy, which should be sent for immunohistochemistry to detect CMV antigen and viral culture.145 Herpes simplex virus infection rarely causes intestinal disease except for esophageal infection.146 Although astrovirus was the most frequently detected enteric virus in a recent study,124 commercial tests are not yet available for detecting this virus, which does not appear to produce serious infection. Of note, rotavirus, adenovirus, and Coxsackie virus are causes of sporadic diarrhea that are detectable by enzyme-linked immunosorbent assay (ELISA) or stool culture.147–149 Infectious diarrhea related to Salmonella, Shigella, and Campylobacter species are very rare in hospitalized BMT patients. Diarrhea related to parasites (Cryptosporidium, Giardia lamblia, Entamoeba histolytica) is also a rare cause of diarrhea, and most of these patients are infected pretransplantation.150–152 Another treatable cause of diarrhea includes overgrowth with Candida albicans.153,154
Diarrhea occurs in up to 20% of patients who receive antibiotics and is usually a self-limited process.61 Most patients with antibiotic-associated diarrhea have normal-appearing or minimally erythematous colorectal mucosa at endoscopy. Carbohydrates that are incompletely absorbed by the small intestine reach the colon where anaerobic flora normally converts them to short-chain fatty acids. In patients receiving broad-spectrum antibiotics, the colonic flora are unable to perform this function, and diarrhea results. Similary, patients with GVHD or enteric infections that involve the small intestine often malabsorb carbohydrate due to loss of mucosal brush-border disaccharidases, resulting in diarrhea following oral intake.155 Other causes of diarrhea in cancer patients include postresection diarrhea and neuroendocrine tumors with production of hormones stimulating net fluid secretion (carcinoid, VIPoma, somatostatinoma). Iatrogenic forms of diarrhea are not infrequently encountered in clinical practice. Diarrhea can occur secondary to intake of oral magnesium salts and/or magnesium-containing antacids. In addition, prokinetic agents such as metoclopramide or cisapride can contribute to or produce diarrhea. In cases of unexplained diarrhea, a careful review of a patient’s medication list is warranted. In the inpatient setting, orders for laxatives or stool softeners may not have been canceled despite the onset of diarrhea.
The objective of antidiarrheal therapy is to reduce fluid loss from the gut by inhibiting intestinal secretion, promoting absorption, and decreasing intestinal motility. Opioid agonists are the most commonly used agents. In noninfectious diarrhea, including that induced by the conditioning regimen, opioid agonists including loperamide at doses up to 4 mg taken every 6 hours orally or diphenoxylate, can be used.156 Diphenoxylate is an opioid anticholingeric combination that can be given at doses of up to two tablets every 6 hours. Careful observation of patients receiving these drugs is warranted due to their impairment of intestinal motility. In patients with diarrhea that is refractory to opioid agonists and other conventional treatments, octreotide, has also been shown to be effective therapy, should be considered.157–159 A consensus panel has put forth guidelines for octreotide therapy for secretory diarrhea related to chemotherapy, radiation, or GVHD that is refractory to conventional therapy.160 Patients should receive fluid and electrolyte replacement and be kept nil per os (NPO) until symptoms are improved. Prompt and aggressive antidiarrheal therapy can significantly enhance the quality of life of cancer patients and reduce hospital admissions, thereby reducing health-care expenditures.
Veno-occlusive disease (VOD) is a clinical syndrome occurring in BMT patients and is characterized by the triad of jaundice, tender hepatomegaly, and weight gain.161–164 Fluid retention and weight gain are usually the first signs of VOD and occur 10 to 20 days following conditioning chemotherapy.163 Patients subsequently develop tender hepatomegaly and hyperbilirubinemia. The onset of rapid weight gain and jaundice in the first 2 weeks post BMT are the most important clues as to the diagnosis of VOD. Conditions that can mimic VOD include (1) sepsis requiring aggressive fluid resuscitation and significant cholestasis; (2) hyperacute hepatic GVHD in a septic patient, and (3) passive congestion of the liver secondary to congestive heart failure.165,166 In many cases, the hepatic dysfunction in BMT patients is multifactorial and does not meet classic criteria for a single diagnosis. In cases where acute GVHD needs to be excluded and/or the diagnosis is uncertain, a liver biopsy should be performed. These patients are often thrombocytopenic, and in this circumstance, transjugular liver biopsies are safer than those done percutaneously.167,168 Using this method, an adequate tissue sample can be obtained. With available expertise, a hepatic venous pressure gradient can be determined at the time of this procedure that, when above 10 mm Hg, is virtually diagnostic of VOD in the early post-transplantation period.167,169 Although not specific for VOD, laboratory tests reveal elevations in total bilirubin and alkaline phosphatase and to a lesser extent, transaminases. Ultrasonography or CT demonstrates hepatomegaly, ascites, and attenuated venous flow, which are supportive of the diagnosis of VOD. Ultrasonography with Doppler flow demonstrates reduced hepatic venous bloodflow. However, these findings are not sufficiently sensitive to establish a diagnosis of VOD early in the course of disease.
The pathogenesis of VOD is not well understood but is believed to be caused by the combination of chemotherapy and irradiation.163,170,171 Elevations in serum aminotransferase (AST) prior to BMT have been shown to be an independent risk factor for VOD.161,162 The clinical outcome of patients with VOD depends on the disease severity. Those with mild and moderate (requiring diuretics) VOD often recover completely. Severe VOD is associated with multi-organ failure and is usually fatal.163 A mathematical model developed to predict the outcome of VOD considers the increase in body weight and serum bilirubin in the first 14 days post BMT.172 In addition, data indicate that higher hepatic venous wedge pressures are associated with worse patient outcomes.169 Histologic findings in liver biopsy specimens include subendothelial edema producing narrowing of terminal hepatic venules, dilation and engorgement of sinusoids, endothelial destruction, and necrosis of centrizonal hepatocytes.173,174 Late microscopic changes include sclerosis of venular walls, fibrosis of vascular lumens, and collagen disposition in the sinusoids.175 The number of histologic abnormalities has been shown to correlate strongly with the clinical severity of VOD.174
Patients with VOD require careful management of their volume status and use of diuretics for fluid overload; care is otherwise supportive.163 Newer treatment strategies are being evaluated, but all remain investigational. These include studies of thrombolytic therapy176,177 and use of Defibrotide.178 Although liver transplantation has been performed in selected patients with severe VOD,179,180 this is not a reasonable option in patients who are at high risk of disease relapse. Transhepatic stents have been placed in a limited number of patients with VOD, and those with severe VOD have not benefited.181,182
GVHD will develop in a proportion of allogeneic recipients undergoing hematopoietic cell transplantation despite immunosuppressive prophylaxis. GVHD generally develops after day 15 after BMT, which corresponds to the timing of engraftment. Patients with hepatic GVHD develop a progressive rise in liver function tests including alkaline phosphatase, total bilirubin, and serum aminotransferases.183 Hepatic GVHD frequently occurs in patients with GVHD involving the intestine and/or skin, and the presence of either or both with cholestasis strongly suggests the diagnosis. In such patients, a liver biopsy can often be deferred due to the fact that treatment is already required for other organ involvement. In cases where the diagnosis is in question, liver biopsy is needed to establish the diagnosis of GVHD and to exclude other causes of liver function test abnormalities in allogeneic recipients, including drug toxicity, infectious hepatitis, VOD, and sepsis. At liver biopsy, characteristic findings include ductular epithelial cell loss secondary to apoptosis and infiltration of bile ducts by lymphocytes.184,185 Of note, leukopenic patients may have minimal leukocyte infiltration.184 Although bile duct abnormalities can be seen with other conditions, ductular epithelial cell dropout by apoptosis, as seen at light microscopy, is characteristic of hepatic GVHD.184 Acute GVHD of the liver can be treated by adding prednisone to the immunosuppressive regimen. However, in a large retrospective study,186 only 30% of patients with hepatic GVHD were shown to have resolution of liver function abnormalities after initial treatment. Additionally, more than one-half of patients with acute hepatic GVHD will develop chronic GVHD of the liver.187
In some cases, acute infectious hepatitis can be difficult to distinguish from GVHD. Accurate diagnosis is important in that the treatment strategies are markedly different for these conditions. In these cases, liver biopsy can be very useful in distinguishing these entities. In the occasional patient, both processes may co-exist. The development of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection after BMT often represents reactivation of a latent infection, or alternately, the virus may be acquired from an infected donor.188 These patients who are receiving immunosuppressive medications may have normal or mildly elevated serum transaminases despite the finding of high HBV DNA titers. When immunosuppressive therapy is tapered, a rise in transaminases will occur in these patients, representing virally mediated hepatocellular injury.189,190 Such flares of hepatitis can be fulminant in the case of hepatitis B but only rarely with hepatitis C.191 Antifungal prophylaxis in BMT patients has markedly reduced the incidence of hepatic fungal infections, which are generally the result of Candida species.192 As a result, these infections are infrequently encountered in the BMT patient population treated with antifungal prophylaxis.
Acute pancreatitis in patients with underlying cancer can be caused by conditions found in the general population such as gallstones or alcoholism or as a complication of endoscopic retrograde cholangiopancreatography (ERCP). Acute pancreatitis may also occur secondary to medications such as metronidazole, cortiosteroids, and furosemide. During the course of chemotherapy, pancreatitis has been reported with azathioprine,193 ifosfamide,194 prednisone,195 L-asparaginase,196 cytosine arabinoside,197 and various regimens of combination chemotherapy including Vinca alkaloids, methotrexate, mitomycin C, 5-FU, cyclophosphamide, cisplatin, and bleomycin.198–200 Metastases to regional lymph nodes, producing enlargement and related ductal obstruction, can cause pancreatitis, as can metastasis to the pancreas itself.201,202 Pancreatitis has also been reported as a complication of tumor lysis in patients with lymphomatous involvement of the pancreas and as a presenting manifestation of immunoblastic lymphoma203 or as a result of transcatheter embolization of hepatocellular carcinoma.204 Causes of pancreatitis in immunocompromised patients include disseminated infections with CMV, VZV, and adenovirus.205,206 Symptomatic pancreatitis is uncommon in BMT patients, although an autopsy study of such patients found pathologic evidence of pancreatitis in 28% of 184 patients.207
In the evaluation of abdominal pain in patients with cancer, pancreatitis should be considered in the differential diagnosis. A careful medication history should be obtained. Serum amylase and lipase levels may be elevated and may aid in diagnosis and monitoring.
Imaging studies that may facilitate the diagnosis include ultrasonography that can detect gallstones or dilation of the common bile duct as a result of choledocholithiasis. Abdominal CT is also useful for diagnosis and in assessing the severity of the inflammatory process and evaluating for associated complications.208
Patients receiving external beam radiation to the abdomen and pelvis for therapy of gynecologic, genitourinary, gastrointestinal, and other malignancies are at risk for complications of radiotherapy, including acute and chronic intestinal injury. Particularly severe injury has been seen in some patients with cervical cancer treated with both radiation implants and external beam irradiation. Chronic radiation coloproctitis or proctitis develops in some patients as a consequence of mucosal and bowel wall injury that includes fibrosis and obliterative endarteritis with subsequent local tissue ischemia.209 Persistence of symptoms at 3 months postirradiation indicates chronicity, and such patients generally have significant abnormalities of the colorectal mucosa at endoscopy. Symptoms include complaints of abdominal or pelvic discomfort as well as tenesmus. Patients report a frequent urge to defecate, and many report passage of loose stools. These symptoms are more common during radiotherapy or immediately afterward but can become chronic in some patients. Those with chronic injury generally report passage of mucoid material and/or gross blood alone and mixed with feces. Such patients are often referred to gastroenterologists, particularly when rectal bleeding is present. In severe cases of coloproctitis, patients may be transfusion dependent. Endoscopic findings in patients with chronic symptoms has revealed mucosal erythema and edema with a common finding of mucosal telangiectasias.209 The telangiectasias and the surrounding mucosa are often friabile, and in severe cases, spontaneous hemorrhage is observed. Severe cases may also have mucosal ulcers with or without bleeding from the ulcer edge, stricture formation, and in some cases, extensive ulceration with necrotic material. Symptomatic bowel strictures can in some cases be treated with endoscopic dilation. A subset of patients with severe refractory disease requires intestinal diversion or permanent colostomy following resection of the affected bowel.209,210
To date, there is no standard or generally accepted treatment for radiation coloproctitis. Medical treatments evaluated have been similar to those used for ulcerative colitis and include systemic therapies211 and topical steroid212 or mesalamine212,213 enemas. Results of these studies have, in general, been disappointing.211,213,214 In our experience, patient compliance and retention of mesalamine enemas can produce a modest symptomatic benefit in those without severe injury, as assessed endoscopically. However, extended follow-up has not been performed. Sucralfate, evaluated in a phase III trial for chronic radiation proctitis, failed to show symptomatic benefit.215 An alternative treatment includes short chain-fatty acid (SCFA) enemas, which have been shown to be efficacious in the treatment of patients with diversion colitis216 as well as distal ulcerative colitis.217,218 Short-chain fatty acids, including sodium butyrate, are produced in the large intestine through fermentation of dietary fiber by endogenous bacterial flora.219 SCFA are readily absorbed in the bowel and are the preferred metabolic substrate for colonocytes.220 The authors221 and others222 have shown that SCFA enemas can reduce rectal bleeding in short-term studies in patients with chronic radiation proctitis, although Talley and colleagues223 did not find a benefit versus placebo. Other medical therapies include rectal instillation of dilute formalin.224 Hyperbaric oxygen treatment has been shown to be beneficial in some studies.225 Endoscopic therapies for bleeding associated with radiation proctitis include use of argon beam coagulation226 and Nd:YAG laser treatment.227
Complications involving the anus and rectum are not infrequently encountered in patients with cancer. The subset of patients in whom these problems are most prevalent includes those with acute leukemia undergoing chemotherapy. We will briefly consider only the management of hemorrhoids and fistula in ano since management of perianal infections is covered elsewhere.
External hemorrhoids consist of dilated venules of the inferior hemorrhoidal plexus covered by squamous epithelium located distal to the dentate line. They are generally asymptomatic unless a thrombosis develops. Symptoms include perianal swelling and severe pain, usually persisting for several days. In general, diagnosis is easily made by inspection and (rarely) gentle anoscopy. Conservative treatment includes hot sitz baths, mild analgesics, maintenance of soft bowel movements with a bulk diet, and confinement to bed for a few days if possible.228 In general, the majority of leukemic patients with acutely prolapsed, nonthrombosed hemorrhoids acute anal fissures respond well to sitz baths, suppositories, and stool softeners, as do their nonleukemic counterparts. In the unlikely event that these conservative measures are not adequate and marked bleeding from an ulcerated hemorrhoid should occur, one should try to avoid procedures that may cause marked tissue sloughing or infections in this often neutropenic population. Procedures to avoid include rubber-band ligation, injection of sclerosing agents, and infrared photocoagulation.
Fistula in ano usually results from the incomplete healing of a drained anorectal abscess. The space between the internal and external anal sphincters is called the intersphincter plane. This space contains anal glands that may become obstructed due to the accumulation of fecal and foreign debris, thus providing the necessary combination of stasis, bacterial accumulation, and chronicity to account for the development of a fistulous abscess. Once established, a fistula in ano rarely heals spontaneously. Definitive surgical correction should be planned as soon as possible after hematologic recovery to avoid the almost inevitable recurrence of infection with the next course of chemotherapy.228
