© Springer Science+Business Media New York 2016
Ellen F. Manzullo, Carmen Esther Gonzalez, Carmen P. Escalante and Sai-Ching J. Yeung (eds.)Oncologic EmergenciesMD Anderson Cancer Care Series10.1007/978-1-4939-3188-0_55. Gastrointestinal Emergencies in the Oncology Patient
(1)
Department of General Internal Medicine, Unit 1465, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
(2)
Department of General Internal Medicine, Unit 1462, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
(3)
Department of Critical Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Keywords
NauseaVomitingSecretory diarrheaInfectious diarrheaChemoradiationGraft-versus-host diseaseGastrointestinal bleedingSpontaneous bacterial peritonitisAcute cholangitisMalignant bowel obstructionEncephalopathyChapter Overview
A large number of cancer patients present with gastrointestinal (GI) complaints owing to either the disease process or complications of treatment. Nausea and vomiting occur frequently and require prompt intervention to avoid dehydration, delays in treatment, and lack of compliance. Different diagnostic considerations must be kept in mind, including chemoradiation, obstruction at any level of the GI tract, brain metastasis, and metabolic causes. Diarrhea is encountered frequently and may be related to infection, chemotherapy, radiation therapy, graft-versus-host disease (GVHD), secretory tumors, or neutropenia in the cancer patient. In addition, malignant bowel obstruction (MBO) is common in patients with intra-abdominal or extra-abdominal malignancies. Treatment of such obstructions varies according to the etiology and patient’s performance status. The different modalities of therapy for them are discussed in this chapter. GI bleeding, hepatobiliary problems such as acute cholangitis, spontaneous bacterial peritonitis, ascites, and their treatment in cancer patients are also described. Recognizing, establishing an accurate diagnosis of, and promptly intervening for these clinical situations once a physician is presented with them is of paramount importance, as they may significantly affect the patient’s survival.
Introduction
Most patients with cancer incur GI complications over the course of their disease. This may result from the disease itself or its treatment , and these complications may be emergent. Symptomatic relief of nausea, vomiting, anorexia, or constipation can bring valuable relief from suffering, whereas some problems, such as cholangitis, bleeding, and bowel obstruction, may be life-threatening. This chapter reviews these conditions and their management.
Nausea and Vomiting
Nausea is a very disagreeable symptom even when unaccompanied by vomiting and can cause noncompliance. A common misconception is that the advent of new antiemetics in the 1980s eliminated the problem of nausea and vomiting in the cancer patient receiving chemotherapy.
The genesis of nausea and vomiting has different etiologies in the cancer patient, including but not limited to chemotherapy; radiation therapy; the cancer itself; bowel obstruction; metabolic upset such as hypercalcemia, hyperglycemia, and uremia; and infections such as gastroenteritis . Gastroparesis secondary to cancer, chemotherapy, or diabetes should be considered. A thorough history and physical examination will clarify the possibilities and direct work-up. Special consideration should be given to the possibility of vestibular dysfunction and brain metastasis in patients with intractable nausea and vomiting.
Radiation therapy may be responsible for nausea and vomiting depending on the site, dosage, and fractionation schedule. These complications are expected in patients undergoing total body, half-body, or abdominal irradiation and are even more likely in those receiving concomitant chemotherapy.
Chemotherapy-induced nausea is subdivided into acute, delayed, and anticipatory categories. Acute onset occurs within 2 h, peaks at 4–6 h, and resolves by 24 h. Delayed onset occurs after 24 h and may persist for days. Certain agents , such as cisplatin, carboplatin, cyclophosphamide, and doxorubicin, are especially potent in this regard.
Anticipatory nausea is caused by a conditioned reflex (Pavlovian conditioning) . It is said to be more common in female and younger patients than in male and older ones. Curiously, heavy alcohol consumption lowers susceptibility to this type of nausea. Previous chemotherapy-related nausea is the most potent predisposing factor. Prophylaxis for nausea is the best way to prevent it.
Although the dosage and rate and route of administration of a chemotherapeutic drug are important factors, the inherent emetogenic potential of the agent best predicts nausea. The National Comprehensive Cancer Network classifies agents into high, moderate, low, and minimal risk categories with corresponding emesis prevention protocols (Ettinger et al. 2012).
Complications of nausea and vomiting include dehydration, electrolyte imbalance, and weight loss. Nausea in the cancer patient may be caused by medications other than those used in chemotherapy , such as opiates, digoxin, and many others. The emetic reflex is located in the nucleus tractus solitarius in the brain stem and the chemoreceptor trigger zone in the floor of the fourth ventricle. Circulating chemicals stimulate the chemoreceptor trigger zone, which in turn activates the vomiting center, which also receives afferents from the cerebral cortex, vestibular apparatus, and GI tract via the splanchnic tracts and vagus nerve.
Treatment
A variety of agents are available for treatment of nausea. The 5-HT3 antagonists , which were introduced in the 1980s, are very efficacious. Side effects of these agents are acceptable and include headache, asthenia, constipation, and dizziness. Overall, the 5-HT3 antagonists are equally effective, although clinical experience suggests that one may work in a patient in whom the others do not. Researchers have demonstrated the efficacy of palonosetron in particular in the prevention of delayed nausea in several multicenter, randomized, double-blind phase 3 trials (Aapro 2007; Yang and Scott 2009).
Aprepitant, a neurokinin-1 receptor inhibitor , has exhibited efficacy in the control of delayed nausea when given as a single agent. It also decreases the incidence of acute and delayed nausea and vomiting when used in conjunction with dexamethasone and a 5-HT3 antagonist.
Targeting the different receptors involved in the genesis of nausea is the rationale behind concomitant use of different agents. In addition to serotonin antagonists and steroids , the most frequently used medications in treatment of nausea and vomiting include dopamine receptor antagonists, antipsychotics, phenothiazines, benzodiazepines, and, occasionally, cannabinoids. The use of acupuncture and behavioral therapy may play an important role in nausea treatment in a subset of patients (Ezzo et al. 2006).
In summary, prevention of nausea and vomiting is paramount in cancer patients. The patients must be supported throughout the emetogenic period. Oral and intravenous (IV) routes of serotonin antagonist administration have been equally effective. Physicians are recommended to select an agent and administer it on a predetermined schedule rather than as needed. They also should consider adding an antiemetic from a different drug class for symptom control as well as different agents concomitantly, alternating schedules and routes.
Constipation
Constipation is a particularly common complaint of cancer patients, and relief of it can provide much comfort. It is usually multifactorial in its etiology, providing several possibilities for intervention. In most cases, constipation can be anticipated, and effective countermeasures can be implemented.
A careful history will both establish rapport with the patient with constipation and uncover possible causes of it as well as suggest or rule out other diagnoses. The underlying malignancy, a concomitant illness, the timing of the complaint, a medication history including over-the-counter drugs, and associated symptoms such as nausea, vomiting, and abdominal pain will direct further work-up.
Physical examination of the abdomen will detect distension and tenderness, suggesting a condition requiring surgery. In the absence of neutropenia or other contraindications, hernial orifices and a rectal examination may reveal fecal impaction and bleeding as well as local impairments such as fissures, neoplasms, and thrombosed hemorrhoids. Radiologic evaluation logically follows and includes a flat and upright X-ray of the abdomen and computed tomography (CT) with or without contrast to rule out an obstruction or lesion.
Similarly, clinical findings direct laboratory testing for constipation. The purposes of laboratory evaluation are to rule out another, possibly more immediately threatening condition; confirm the presence and severity of constipation; and suggest the therapeutic approach.
Management of constipation requires attention to fluid intake and electrolyte rebalancing. A dehydrated patient with poor oral intake may need IV replacement . Other therapeutic modalities include stool softeners, osmotic and stimulant laxatives, prostaglandin analogs, enemas, and suppositories . Digital disimpaction may be necessary and remarkably effective and should not be delegated to the unsupervised most junior member of the medical team. In fact, rectal impaction can cause large bowel obstruction with or without overflow incontinence.
Ideal prophylactic measures for constipation include adequate water intake, physical activity, a high-fiber diet, and avoidance of constipating agents. Opioid agonists are inherently constipating via their effect on GI μ-opioid receptors. Cancer patients may be elderly, physically debilitated and immobile, and disinterested in food and may need medications that cause constipation. Additional measures include the use of fiber supplements like methylcellulose, psyllium, and polycarbophil, which are effective for the prevention and reversal of mild constipation. Stool softeners certainly soften the stool, but their ability to evacuate it unaided seems uncertain. Dioctyl calcium sulfosuccinate may be preferable to the sodium equivalent. Stimulant laxatives , such as the anthraquinone senna and the diphenylmethane bisacodyl, are useful on an occasional basis, as they can cause tachyphylaxis. Polyethylene glycol is an osmotic laxative that is well tolerated; 17 g of it in 200 cc of water may be given daily. Lactulose and sorbitol are alternatives, if tolerated. Misoprostol is a prostaglandin E1 analog that stimulates intestinal motility and is well tolerated at 200 mg given every 2 days (Davila and Bresalier 2008).
μ-opioid GI receptor antagonists such as methylnaltrexone have been effective in patients with advanced disease without reversing analgesia, as they do not cross the blood-brain barrier (Thomas et al. 2008).
Diarrhea
Diarrhea is defined in terms of frequency, consistency, and volume of the stool.
Several mechanisms explain diarrhea in the cancer patient, and evaluation of it can be exhausting and costly if relevant clinical information and likely scenarios are not taken into consideration. Diarrhea can be acute—lasting less than 2 weeks—or chronic—lasting more than 4 weeks. This section focuses on common causes of acute diarrhea in the cancer patient.
Infectious Diarrhea
Predisposing conditions for infectious diarrhea in the cancer patient, particularly those associated with neutropenia , are human immunodeficiency virus infection and bone marrow transplantation. Bone marrow transplant recipients are particularly susceptible to viral infections such as those with cytomegalovirus, herpesvirus, astrovirus, adenovirus, and rotavirus. Bacterial infections include those with Escherichia coli 0157 and Yersinia, Salmonella, Shigella, and Campylobacter species. Parasites causing diarrhea in this patient population are unusual but should be considered. The most common infecting parasites are Cryptosporidium species, Entamoeba histolytica, and Giardia lamblia.
Clostridium difficile Infection
The most common form of diarrhea in hospitalized patients is caused by Clostridium difficile and must be considered for any cancer patient undergoing chemotherapy or receiving antibiotics. Diarrhea caused by this infection may be associated with methotrexate, cyclophosphamide, and doxorubicin use, whereas clindamycin traditionally has been the antibiotic most frequently responsible for it. Also, use of fluoroquinolones and cephalosporins is often involved owing to their widespread use. Antibiotic and chemotherapeutic agents disrupt the intestinal flora and mucosa, favoring C. difficile replication and toxin production. C. difficile strains vary in their virulence owing to gene mutations as demonstrated in the production of toxins A and B, which are antigenically distinct (Kelly 2009). Age, general condition, and prolonged hospitalization are risk factors for C. difficile infection. Furthermore, the hospital environment includes resistant species. Hand washing to reduce the spread of infection therefore must be an integral part of the therapeutic approach in cancer patients.
Clinical manifestations of C. difficile infection include profuse diarrhea with a characteristic foul smell, abdominal cramps, fever, ileus, and the presence of pseudomembranous colitis on endoscopic images. Leukocytosis indicated by a white blood cell count greater than 15,000 K/μL, an albumin level less than 2.5 g/dL, admission to the intensive care unit, fever with a temperature of 101 °F or greater, and the presence of pseudomembranous colitis are risk factors. Indicators of infection severity are enzyme immunoassays used to detect the presence of toxins A and B, which are fast, inexpensive, and very specific but lack sensitivity. An infection-negative assay does not supersede a clinical diagnosis. Polymerase chain reaction analysis is highly sensitive and specific but carries the potential for false-positive results. Cultures are recommended only with epidemiologic studies.
Serious complications of C. difficile colitis include toxic megacolon and colonic perforation, which may necessitate a total colectomy. Renal failure, shock, and death have occurred with increasing frequency since the recognition of the new virulent C. difficile strain NAP-1/027. This strain is also responsible for a rise in the infection recurrence rate since 2001 (Johnson 2009).
Treatment of C. difficile infection includes discontinuation of all antibiotics implicated to play a role in the genesis of the infection. This strategy can resolve acute symptoms, but a significant number of patients need additional treatment. Historically, metronidazole and vancomycin have been used as first-line treatment of mild to moderate C. difficile infections at the expense of high recurrence rates and unwanted changes in the intestinal flora. Metronidazole has high systemic absorption; therefore, side effects such as nausea, headache, taste alteration, and peripheral neuropathy are not uncommon (Louie et al. 2011). When using vancomycin , it is given orally at 125 mg 4 times a day for 10 or 14 days. In patients with ileus, 500 mg of vancomycin is delivered to the right colon via enema every 6 h.
Despite adequate treatment, 20–30 % of patients with C. difficile infections experience recurrence. This may be caused by reinfection with a different strain or persistence of infection with the same strain. A first recurrence is treated similarly to the first episode, but for patients with more than one recurrence or severe disease, the use of fidaxomicin , a macrolide antibiotic recently approved for the treatment of recurrent C. difficile infection, is indicated (Louie et al. 2011). Unlike vancomycin, fidaxomicin is bactericidal, and it has a prolonged postantibiotic effect, spares Bacteroides organisms in the fecal flora, and has resulted in markedly reduced recurrence rates. Unfortunately, this favorable clinical profile does not pertain to infections with the virulent NAP-1 strain.
Probiotics (e.g., Saccharomyces boulardii ) may be helpful in combination with vancomycin in treating C. difficile infections. Patients with recurrent or severe refractory infections generally have poor immune response to toxins A and B. IV immune globulin G and immunization may have therapeutic roles, as well. Rifaximin, a minimally absorbed antibiotic, is recommended as a “chaser,” but the epidemic strain B1/NAP-1/027 is increasingly resistant to it. Fecal transplantation , in which donor stool is instilled via a nasogastric tube , seems to be an intriguing therapeutic modality, as it may be effective in reconstituting the gut flora (Johnson 2009).
A newer agent under investigation, the antibacterial lipopeptide CB-315, promises similar advantages but, again , does not seem to be more effective against the NAP-1 strain than other agents (Cubist Pharmaceuticals 2012).
Chemotherapy- and Radiation-Related Diarrhea
Chemotherapy , by virtue of its cytotoxicity in tissues with high metabolic activity such as the small bowel and colon epithelium, causes mucosal damage and alters absorption capability. Chemotherapy-related diarrhea is usually self-limited but is exacerbated by oral intake and may be severe enough to warrant hospitalization. The main therapeutic necessity is to maintain an adequate fluid and electrolyte balance. Some of the more problematic chemotherapeutic agents regarding diarrhea incidence include 5-fluorouracil (5-FU), methotrexate, irinotecan, and cisplatin. Capecitabine is metabolized to 5-FU, and diarrhea is a dose-limiting side effect of it (Davila and Bresalier 2008).
When given with leucovorin, a 5-FU bolus may cause severe symptoms, more so than when given as a continuous infusion. Moreover, risk factors increase susceptibility to diarrhea in patients who receive this treatment. These include female sex, presence of an unresected tumor, previous diarrhea induced by chemotherapy, and use of 5-FU during summer (Davila and Bresalier 2008).
Irinotecan may cause both early—within a few hours after infusion—and late diarrhea. Early diarrhea is mediated by a cholinergic mechanism and is often associated with cramping, salivation, and lacrimation. These symptoms are controlled with the use of loperamide and atropine. The mechanism of irinotecan-induced late diarrhea is poorly understood, as it may happen at any time after infusion and is completely unpredictable but may be mitigated if irinotecan is given every 3 weeks. Combined administration of irinotecan, 5-FU, and leucovorin is particularly troublesome, as is the addition of a 5-FU bolus and leucovin to treatment with oxaliplatin (Davila and Bresalier 2008).
Radiation therapy-induced diarrhea is secondary to mucosal injury and may be worsened by the addition of chemotherapy, especially with 5-FU. Acute diarrhea develops after 1–2 weeks of treatment. Small-bowel involvement causes profuse diarrhea. If prolonged, it may lead to malabsorption and weight loss . Acute radiation proctitis occurs within 6 weeks of therapy and resolves in 6 months. Symptoms include urgency, tenesmus, and bleeding. Chronic diarrhea appears a year or more after exposure to radiation and is characterized by mucosal atrophy and fibrosis . Treatment may require argon plasma coagulation for bleeding. Up to a third of patients with chronic radiation enteritis need surgery for strictures, fistulas, and perforations with significant complications and mortality (Theis et al. 2010).
In the absence of infection, treatment of both chemotherapy- and radiation therapy-related diarrhea should focus on avoiding dehydration, correction of electrolyte imbalances, and, if necessary, aggressive use of antidiarrheal medications such as opioid agonists. Loperamide (Imodium) given initially at 4 mg followed by 2 mg every 4 h until the diarrhea subsides and 2 diphenoxylate (Lomotil) tablets taken every 6 h are commonly used. Octreotide , a long-acting synthetic somatostatin (SST) analog, may be used for more refractory cases , and tinctures of opium, paregoric, codeine kaolin, and charcoal are helpful (Eng 2009).
GVHD
The most common cause of diarrhea in hematopoietic transplant recipients, especially allogeneic bone marrow transplant recipients, is GVHD. Acute GVHD was traditionally thought to occur within 100 days after hematopoietic stem cell transplantation, with chronic GVHD developing thereafter. The recent emphasis has been on the histologic pattern of GVHD. Acute GVHD exhibits essentially the features of acute inflammation and of donor lymphocytes attacking recipient antigens, whereas chronic GVHD features the later fibrosing consequences. Biopsy analysis of the stomach, small bowel, and rectal mucosa in patients with acute GVHD characteristically demonstrates apoptosis, and vacuolar degeneration may be present in the skin (Washington and Jagasia 2009).
Acute GVHD attacks the GI tract , causing secretory diarrhea with watery stool that may be bloody. Nausea, vomiting, cramping, weight loss, and dysphagia are also associated symptoms (Akpek et al. 2003). Other manifestations include maculopapular/papular skin rash and hepatitis. GVHD may be mild to severe depending on the degree of human leukocyte antigen disparity. These very fragile patients are subject to intensive pretransplant preparation, and the full range of diagnostic possibilities must be entertained. More than one problem may be present.
In patients with chronic GVHD, the esophagus is frequently involved. Fibrosis may cause webs, strictures, and dysphagia. Obstructive lung disease, cholestasis, and scleroderma-like skin findings are observed. Biopsy analysis of skin or components of the GI tract is helpful. An acute GVHD episode may flare and confuse the picture, and infection is still the most common cause of death (Akpek et al. 2003). Treatment of acute GVHD consists of the use of steroids. Methylprednisolone (2 mg/kg/day) is effective in the majority of cases, but mortality rates remain high (Kurbegov and Giralt 2006).
Secretory Diarrhea
Secretory diarrhea is caused by abnormal ion transport and subsequent water secretion. Patients with neuroendocrine tumors deserve special consideration.
Neuroendocrine Tumors and Diarrhea
The cells of the neuroendocrine system are located throughout the body. Formerly known as enterochromaffin cells , they must be located close to their target tissues, as their active secretions are rapidly metabolized. Even the most common neuroendocrine tumor type, carcinoid, is unusual, and VIPomas are exceedingly rare. These tumors secrete a variety of active substances that account for the various syndromes seen in patients with these lesions.
Carcinoids are the earliest described and easily most common neuroendocrine tumors. They may be components of multiple endocrine neoplasia type 1. Carcinoids secrete serotonin, motilin, and substance P, with subsequent increased motility in the small and large intestines. Ten percent of carcinoid patients exhibit the syndrome requiring liver or bone metastases or a pulmonary tumor origin. This allows for active substances to escape liver metabolism as they bypass the portal circulation (Yeung and Gagel 2009). Increased serotonin levels are detected using 24-hour 5-hydroxyindoleacetic acid measurement, and lesions are localized using imaging studies, including indium pentetreotide scintigraphy. Localized disease is treated surgically. Debulking and use of I-131 SST analogs as targeted therapy may provide symptomatic relief. These analogs control symptoms as described below (Yeung and Gagel 2009). VIPoma syndrome includes watery diarrhea, hypokalemia, and achlorhydria. Patients with this syndrome have elevated serum vasoactive intestinal peptide levels. The majority of peptides are found in the pancreas, with the rest found in the duodenum and retroperitoneum. A carcinoid is a slow-growing tumor, and many carcinoids are treated with surgery. Even hepatic metastases of carcinoids may be resectable or amenable to embolization. Treatment with SST analogs provides relief in nonresectable cases (Yeung and Gagel 2009).
Standard chemotherapy is both ineffective against carcinoids and associated with severe toxic effects. On the other hand, SST analogs provide symptomatic relief and may inhibit the growth of these tumors. SST inhibits all known GI hormones via binding to a class of membrane receptors. Tumors arising in SST target tissue express these receptors unless they are poorly differentiated. However, SST is quickly metabolized and not useful clinically. Octreotide and lantreotide are analogs that combine antitumor activity with metabolic stability. Long-acting versions of these agents that are self-administered have sustained activity levels with mild side effects. They are useful in treating acromegaly, pancreatic islet cell tumors, and GI neuroendocrine tumors. These agents also prevent or improve flushing and diarrhea in patients with carcinoid syndrome. Furthermore, they are equally effective against vasoactive intestinal peptide diarrhea (Modlin et al. 2010).
Octreotide LAR injected at 30–60 mg every 4 weeks has replaced daily dosing of this agent. Lantreotide Autogel administered at 60, 90, or 120 mg monthly via deep subcutaneous injection is equally effective. Pasireotide is a newer agent that may be beneficial in patients with tumors resistant to the other agents (Modlin et al. 2010).
Neutropenic Enterocolitis (Typhlitis)
Typhlitis is characterized by right lower quadrant pain and fever in patients with neutropenia following administration of cytotoxic agents. It occurs most frequently in patients with hematologic malignancies : acute leukemia, myelodysplastic syndrome, or multiple myeloma. It is also encountered in patients with any type of immunodeficiency , such as acquired immunodeficiency syndrome, and with granulocytopenia of any origin.
Neutropenic enterocolitis results from a number of factors that coalesce to induce disease. Mucosal injury caused by cytotoxic drugs in association with an abnormal host response and infiltration of the intestinal mucosa by leukemic cells favor bacterial invasion and the production of endotoxins and necrosis. The cecum is almost always involved; the terminal ileum also may be affected. The cecum is highly distensible and has a relatively poor blood supply. Pathologic findings have revealed edema and inflammation of the intestinal wall, hemorrhages, and necrosis. Physicians have isolated several bacteria from peritoneal fluid and surgical specimens obtained from patients with neutropenic enterocolitis, most frequently Clostridium septicum and gram-negative rods (Davila and Bresalier 2008).
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