Gastrointestinal mucositis

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Seminars in Oncology Nursing, Vol 20, No 1 (February), 2004: pp 38-47

OBJECTIVE: To review the management of radiotherapy- and chemotherapyinduced gastrointestinal mucositis.

DATA SOURCE:

GASTROINTESTINAL MUCOSITIS

Articles and research studies.

CONCLUSION: Gastrointestinal damage is becoming a common dose-limiting toxicity. However, there is only limited research into the mechanism and possible treatment of this toxicity.

IMPLICATIONS PRACTICE:

FOR

NURSING

It is important to document the frequency and severity of gastrointestinal mucositis, and to alleviate symptoms wherever possible.

Dorothy M.K. Keefe, MD, FRACP: Senior Consultant Medical Oncologist, Department of Medical Oncology, Royal Adelaide Hospital and the Department of Medicine, University of Adelaide, South Australia. Rachel J. Gibson, BHSc(Hons): Research Assistant, Department of Medical Oncology, Royal Adelaide Hospital and the Department of Medicine, University of Adelaide, South Australia. Martin HauerJensen, MD, PhD, FACS: Professor of Surgery & Pathology, Departments of Surgery and Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR. Supported by National Institutes of Health grant nos. CA83719 (M.H.-J.) and CA71382 (M.H.-J.) and the Cancer Council of South Australia (D.M.K.). In addition, support was provided by Amgen (KGF to D.M.K. and R.J.G.) and Pharmacia (Irinotecan to D.M.K. and R.J.G.). Address reprint requests to Dorothy Keefe, MD, FRACP, Department of Medical Oncology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000.

© 2004 Elsevier Inc. All rights reserved. 0749-2081/04/2001-0007$30.00/0 doi:10.1053/S0749-2081(03)00138-4

DOROTHY M.K. KEEFE, RACHEL J. GIBSON, MARTIN HAUER-JENSEN

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AND

ASTROINTESTINAL mucositis (GIM) has for many years been the so-called poor relation of oral mucositis with regards to research into its mechanism and treatment. One reason for this is that the term “mucositis” covers the entire area from the esophagus to the anus via the stomach, small bowel, colon, and rectum, all areas that are relatively inaccessible to study.1,2 Gastrointestinal mucositis may be caused by radiation therapy and chemotherapy, as well as by combination therapy. Radiation-induced damage occurs mainly at the site of delivery; whereas, chemotherapy-induced GIM is generalized throughout the gastrointestinal tract. With the recent advances in bone marrow support, supportive care, and more accurate targeting of radiotherapy to reduce exposure of normal tissues surrounding the tumor, higher doses of both radiotherapy and chemotherapy can be used in an attempt to increase cure rates. The increase in chemotherapy intensity has led to increased gastrointestinal (GI) toxicity in tissues with high cell turnover, such as the gastrointestinal tract (GIT).1-3 Despite the prominence of GIM, to date there is no successful treatment for these unpleasant side effects, and patients must largely rely on palliation of symptoms including antidiarrheal agents, antiemetics and analgesics.1-4 Historically, the susceptibility of GI mucosa to toxicity has been attributed to the nonspecific effects of tumoricidal agents on rapidly dividing cells within the normal epithelium.5-7 However, it is likely that many of the observed changes are the consequence of a complex network of primary and secondary biological events. Furthermore, it is quite possible that differential effects of major transcription factors such as NF-␬␤, between normal and tumor cells, is a significant factor in preferential injury.8 The first case of GI radiation mucositis was described in 1897,9 just 2 years after the discovery of the x-ray. There has been significant interest in radiation-induced GIM for many decades, and the mechanisms of radiation-induced injury in the various regions of the GIT are somewhat better understood than those of chemotherapy-induced injury. In the last decade, considerable work has also been performed on investigating the morphologic changes in response to chemotherapy in both the human,1,5 and

GASTROINTESTINAL MUCOSITIS

rodent GIT,10-12 and in the oral cavity.13-16 However, to date these investigations have separated the GIT into the oral and esophageal mucosa and the remainder of the tract, with no investigations to date having investigated the entire GIT from mouth to anus. There are at least two major reasons for this parochial approach to past studies of mucositis. First, while both the upper and lower GIT are lined with mucosa, the tissue type is different. The upper GIT consists of a renewing stratified squamous mucosa, whereas the lower GIT is primarily columnar epithelium. As a consequence, the kinetics of mucositis in the two areas is vastly different, as are the clinical endpoints. Second, the ease with which the oral mucosa can be inspected and studied in in vivo models has been an asset compared with the remainder of the tract. However, because the mouth and the rest of the GIT have the same embryologic route of development, with differences in differentiation at various sites being necessary to carry out specialized functions, it is more likely that the similarities will outweigh the differences throughout the oral cavity and GIT. Mechanistically, therefore, it seems highly likely that the biological events that result in mucositis are shared throughout the GIT. While the kinetics of mucosal injury vary, the ability to identify each mechanistic step in the development of mucosal injury provides a potential interventional opportunity that could be applicable to any component of the GIT. The recent review of the literature conducted by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and The International Society of Oral Oncology has highlighted the problems in GIM research, namely the lack of evidence in the literature for any interventions, overlying a basic lack of definition of mechanisms on which to base potential therapies. With the recent advances in understanding of the pathobiology of oral mucositis, it is likely that mucositis in the rest of the GIT is perhaps even more complex. However, this article will confine itself to the discussion of mucositis distal to the mouth. For the purposes of clarity, we will distinguish between chemotherapy- and radiotherapy-induced damage. However, because chemotherapy and radiotherapy are often given together, some comment needs to be made. It is well known that chemotherapy can exacerbate radiation-induced damage, but there has been very little study of the combined injuries. Chemo-

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therapy tends to be given for a small number of days every few weeks; whereas radiotherapy is usually given on a daily basis for several weeks. In terms of understanding the mechanism of injury, it is important to recognize that the tissue that was treated on day 1 is not the same tissue that was treated on subsequent days. As discussed below, the mechanism of radiation-induced damage in the various regions of the GIT is better understood than that of chemotherapy-induced damage.

GASTROINTESTINAL RADIATION TOXICITY

D

espite recent advances in treatment planning and radiation delivery technology, normal tissue toxicity remains the principal dose-limiting factor in clinical radiotherapy. As is the case for chemotherapy-induced injury, the mechanisms and pathophysiology of radiation injury in the various segments of the GI tract are similar in many respects, but there are also important anatomic and physiologic differences. Hence, clinical presentation and management strategies are, to some extent different, depending on the segment of the GI tract affected by radiation toxicity. Quantitatively and clinically, radiation toxicities of the small intestine, colon, and rectum are more important than toxicities of the esophagus and stomach. Based on the time between radiation therapy and clinical presentation of symptoms of radiation toxicity, radiation toxicity is classified as acute (up to 3 months after radiation therapy) or chronic (more than 3 months after radiation therapy). The rapidly proliferating epithelium is the primary target cell compartment for acute radiation toxicity in alimentary tract organs. Radiationinduced epithelial cell death leads to breakdown of the normal mucosal barrier, allowing penetration of antigens, bacterial products, and digestive enzymes from the lumen into the deeper tissues, thus initiating an intense inflammatory response. The mechanisms of chronic radiation toxicity are more complex than those of acute radiation toxicity. Although there are changes in the intestinal wall, chronic radiation toxicity is primarily a disorder of blood vessels and connective tissue. Hence, the hallmark features of chronic GI radiation injury are vascular damage and relentless, progressive fibrosis. A comprehensive review of

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radiation injury of GI organs is beyond the scope of this article, but can be found elsewhere.17-19 Esophagus The esophagus is lined by a rapidly proliferating, highly radioresponsive, stratified squamous epithelium. Most patients who undergo radiation therapy of tumors in the chest, mediastinum, or neck, with parts of the esophagus in the radiation field, experience symptoms of acute radiation esophagitis. The main clinical manifestations of acute radiation esophagitis are dysphagia, odynophagia (painful swallowing), and substernal chest pain. With conventionally fractionated radiation therapy, these symptoms usually begin toward the end of the second week of treatment. The symptoms may be quite severe, but usually resolve quickly on completion of radiation therapy. Delayed (chronic) radiation-induced esophageal complications, mostly caused by stricture formation or fibrosis with esophageal dysmotility, are uncommon, but problematic when they occur. Patients with acute radiation-induced esophagitis should change their diet to a soft, bland diet and avoid irritating food and liquids, including acidic drinks and alcohol. Medical management consists of the topical use of local anesthetics, spasmolytics, analgesic drugs, and treatment of acid reflux. In some patients, the symptoms of acute radiation-induced esophagitis are sufficiently severe to require a temporary interruption of the radiation treatment or modification of the original treatment plan. Few patients develop chronic esophageal radiation injury, but those that do frequently require repeated dilatation of esophageal strictures. Surgical intervention is rarely indicated. Stomach The stomach is lined by a single layer of columnar epithelium. Radiation toxicity of the stomach presents less of a problem clinically than toxicities in the other alimentary tract organs. Hence, while patients who receive radiation therapy with the stomach in the radiation field often develop dyspepsia and symptomatic gastritis, these symptoms are temporary and usually easily managed. Chronic complications such as gastric ulcers were reported in the past, but are generally not a problem with modern treatment techniques. The clinical management of patients with radiation-induced gastritis follows the general guidelines for gastritis treatment. Patients usually re-

spond well to histamine-2 receptor antagonists or proton pump inhibitors. Small Intestine The columnar epithelium that lines the intestinal mucosa has a rapid turnover rate and exhibits a prominent radiation response, and most patients who receive radiation therapy of abdominal or pelvic malignancies develop symptoms and signs of acute small bowel toxicity. The main clinical features are nausea, abdominal pain, and diarrhea. Nausea generally occurs early in the treatment course, while diarrhea and abdominal pain more often develop 2 to 3 weeks into the treatment course. The acute symptoms usually resolve within 2 to 4 weeks of completing treatment. Symptoms of chronic bowel toxicity present after a latency period, typically 6 months to 3 years after radiation therapy. Patients with chronic bowel injury often have intermittent constipation and diarrhea, and are frequently metabolically deranged and malnourished. In severe cases, progressive intestinal wall fibrosis leads to the development of strictures, while localized areas of ischemia may lead to perforation or fistula formation. Many patients present initially as surgical emergencies with acute intestinal obstruction, fistulas, or bowel perforation. The prognosis of patients suffering from chronic small bowel radiation injury is poor. Surgical intervention carries high postoperative morbidity and mortality, and many patients require supplemental parenteral nutrition. Long-term, persistent or recurrent symptoms are common, and about 10% of patients die as a direct result of radiation enteropathy. Management of acute small bowel radiation toxicity is symptomatic and follows the general principles and guidelines for treating similar symptoms in other situations. Conventional antidiarrheal, antiemetic, spasmolytic, and defoaming agents are mainstays in the treatment of acute bowel toxicity. The efficacy of synthetic somatostatin analogues (eg, octreotide) is superior to that of conventional antidiarrheal drugs,20 and patients who do not respond to first-line antidiarrheal medication should be considered candidates for octreotide therapy. A long-acting somatostatin analogue is currently undergoing clinical testing in the cooperative group setting as a prophylactic strategy to reduce the incidence and severity of radiation-induced diarrhea. In patients where the effect of conventional anti-

GASTROINTESTINAL MUCOSITIS

emetics is unsatisfactory, 5-HT3 antagonists or NK1 antagonists may relieve nausea and vomiting. Chronic radiation enteropathy, except when complicated by intestinal obstruction, perforation, or fistula formation, is usually managed nonoperatively. When patients present with symptoms suggesting chronic radiation enteropathy, it is important to rule out other intra-abdominal conditions, including cancer recurrence. The management of patients with chronic radiation enteropathy should be highly individualized and directed toward specific underlying abnormalities. A discussion of the diagnosis and management principles in chronic radiation enteropathy has been published elsewhere.21 The main indications for surgical intervention are complications, such as intestinal obstruction, perforation, and fistula formation. In these patients, there is frequently delayed wound healing because of the combination of poor nutritional status and radiation-induced changes in intestine and mesentery. Hence, surgery carries a high risk of anastomotic dehiscence, iatrogenic fistulas, and other complications. Fibrotic strictures are dealt with by resection of involved intestinal segments, intestinal bypass procedures, enterostomy, or stricturoplasty in select patients.22 A key consideration is the preservation of intestinal length because many patients require repeated surgery and are at risk for eventually ending up with short-gut syndrome. Patients with radiation-induced fistulae pose particularly challenging problems. Radiation-induced fistulae almost never heal on conservative management with gut rest, low residue diet, or total parenteral nutrition. Therefore, surgery is usually indicated, as long as the patient has a reasonable performance status. Of note is that, while most patients are malnourished, efforts to improve the patient’s nutritional status preoperatively often fail because of widespread radiation-induced intestinal dysfunction. Colon The clinical manifestations of radiation toxicity of the colon are similar to those of small bowel injury. However, because the primary role of the colon is to absorb water and to serve as fecal conduit, rather than being responsible for the uptake of nutrients, the nutritional impact of colon injury is less than that of small bowel injury. The main symptoms of acute colon toxicity are diarrhea and crampy abdominal pain, while the most common clinical manifestations in patients

41

with chronic radiation injury of the colon are intermittent diarrhea and constipation caused by fibrotic strictures, pseudo-obstruction (functional obstruction without anatomic stricture) because of stiffness and poor peristalsis of the fibrotic bowel wall, and fistula formation. The general principles of management of patients with radiation toxicity of the colon, both acute and chronic, are similar to those discussed above for small bowel toxicity. A unique feature of the colon is that it is accessible by fiberoptic endoscopy, and patients with radiation-induced fibrotic strictures may thus be candidates for endoscopic dilatation. Rectum and Anus Most patients who receive radiation therapy of pelvic tumors have symptoms of acute radiation toxicity of the rectum (radiation proctitis, radiation proctopathy). The main clinical manifestations of acute radiation proctitis are diarrhea, tenesmus (fecal urgency with cramp-like rectal pain), and hematochezia (bloody stools). Moreover, even when almost no small bowel is included in the radiation field, many patients also experience symptoms from the upper abdomen, suggesting neurogenic mechanisms or involvement of circulating mediators. Chronic radiation proctitis is characterized clinically by one or more of the following: frequent or clustered bowel movements, anal discharge, rectal pain, urgency, tenesmus, incontinence, and hematochezia. The clinical picture in the individual patient depends on what type of injury predominates. Hence, bleeding may be the main symptom in patients with diffuse mucosal injury, rectal pain may predominate in patients with chronic rectal ulcers, and urgency may be the chief complaint in patients in whom fibrosis causes loss of rectal compliance and ano-rectal function. Patients are usually more socially disabled by urgency and tenesmus (ie, the need to find a bathroom quickly) than by bloody bowel movements. The management of acute radiation proctitis is symptomatic and follows general principles for treating similar symptoms and signs in other situations. For example, topical anesthetic preparations ameliorate anorectal irritation, while loperamide may be used to reduce tenesmus. Steroidcontaining suppositories may be helpful in some patients. Chronic radiation proctitis is a frequent prob-

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lem among patients who have undergone pelvic radiation therapy. The most obvious symptom is hematochezia, but urgency and frequency can also be prominent and are more difficult to control with medication, and are often more disabling to the patient than bleeding. The first-line therapy for radiation proctitis with bleeding is sucralfate enemas, which often have rapid and dramatic effect. Sucralfate provides a protective “film” in injured mucosa, and increases local levels of fibroblast growth factors and prostaglandins. The effect of sucralfate enemas in the treatment of chronic radiation proctopathy is superior to the commonly used therapy with steroids and 5-aminosalicylic acid.23 Of note is that the benefit of sucralfate in the chronic setting23 is in stark contrast to the lack of effect of this drug in the acute setting.24-27 In patients with hemorrhagic proctitis refractory to sucralfate enemas, bleeding can usually be controlled by local (endoscopic) intervention with topical formalin,28-30 electrocautery,31 laser therapy,32-35 or argon plasma beam coagulation.36-39 Hyperbaric oxygen treatment may be considered in patients with severe symptoms of rectal wall fibrosis or intractable pain caused by rectal ulcers.40,41 Several uncontrolled studies suggest a benefit of hyperbaric oxygen in patients with severe radiation-induced proctitis.42 However, hyperbaric oxygen treatment is logistically demanding, expensive, time-consuming, and not universally available. Moreover, a “placebo”-controlled assessment of the efficacy of hyperbaric oxygen for radiation injury has yet to be performed and, in fact, may never be performed because of the difficulties associated with conducting such a trial. Surgical management of radiation-induced proctitis may be necessary in patients with persistent, transfusion-dependent bleeding refractory to the therapies discussed above, and in patients who have large, nonhealing ulcers, intractable pain, or complications such as strictures or fistulas. Restorative surgery (eg, resection with coloanal anastomosis with or without a colonic Jpouch) is technically demanding, but, in experienced hands, has a reasonable likelihood of success. Restorative surgery is contraindicated in patients with grossly abnormal sphincter function. Proctectomy is as a last resort when more conservative treatment options have failed and when

reparative surgery is unsuccessful or contraindicated.

PROPHYLAXIS

MANAGEMENT OF RADIATION MUCOSITIS

AND

GASTROINTESTINAL

A

plethora of strategies have been tested in preclinical and, to a lesser extent, clinical studies as potential GI radiation response modifiers. Despite promising results with some of these interventions, none are yet in general use in the clinic. Strategies aimed at minimizing normal tissue radiation injury can conveniently be considered as two conceptually different categories: (1) strategies that interfere directly with radiation injury; and (2) strategies aimed at increasing radiation tolerance or enhance the repair capacity of normal tissues. Table 1 lists a few of the interventions that have been studied.43-88 A more complete and in-depth discussion, as applied to GI radiation injury, can be found elsewhere.19

CHEMOTHERAPY-INDUCED GASTROINTESTINAL TOXICITY

T

he common GI symptoms following chemotherapy are heartburn, abdominal pain, diarrhea, bloating and nausea, only the first of which localizes to the site of damage. Histologically, small intestinal damage is more prominent than colonic damage,2 but there are two special cases: first, irinotecan (CPT-11) causes prominent colonic damage,10 and second, newer chemotherapeutic agents such as the taxanes are producing more caecal damage (typhlitis) (Multinational Association of Supportive Care and Cancer/The International Society of Oral Oncology guidelines [Cancer, in press]). Chemotherapy-induced GIM is usually short lived and does not often interrupt treatment, but it compromises the exposure of the GI mucosa to nutrients, reducing absorption, and may cause transient malnutrition.2 In addition, when patients are able to resume eating, chemotherapy-induced damage to the enteroendocrine cell population may interfere with secretion of hormones which aid in digestion.2 However, with drugs such as methotrexate, 5-fluorouracil, and irinotecan, significant gut toxicity can occur, leading to prolonged profuse diarrhea and malnutri-

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TABLE 1. Investigational Strategies for Prophylaxis and Management of Gastrointestinal Radiation Mucositis Free Radical Scavengers and Cytoprotectors

Cytokines and Growth Factors

Amifostine (WR2721, Ethyol) Reduces toxicity in some GIT organs43-49

Keratinocyte growth factor (KGF-1 and KGF-2): Ameliorates oral mucositis in clinical studies and GIT mucositis in animal studies57,58 Anti-TGF-␤ strategies: Preclinical studies promising59

Superoxide dismutase (SOD): Preclinical gene therapy effective in esophagus and intestine50,51

Prostaglandins and prostaglandin analogues: Protection in animal models.52-55 some evidence in patients56

tion. This may be further exacerbated by dairy products, suggesting an induced increase in lactose intolerance. Esophagus Many patients undergoing chemotherapy with agents such as methotrexate, 5-fluorouracil, or the taxanes develop esophagitis with dysphagia, odynophagia, and retrosternal chest pain, which can start within a few days of chemotherapy, and usually settles once chemotherapy is complete. It is treated with histamine-2 (H2)-blockers or proton pump inhibitors, depending on severity,89 and rarely delays treatment. The combination of chemotherapy and radiotherapy, however, can induce severe esophagitis (see discussion on radiation above). The use of either ranitidine or omeprazole is recommended for the prophylactic reduction of epigastric pain and heartburn following treatment with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) and folinic acid chemotherapy (level II, grade A evidence). In two randomized controlled trials led by the same principal investigator,89,90 omeprazole reduced ulcers, epigastric pain, and heartburn,96 and ranitidine reduced ul-

Diets and Nutrients

Other Strategies

Elemental diets: Effective in animal studies, mixed results in clinical trials.60-65

Acetylsalicylic acid (ASA) and NSAIDS: ASA may be of some benefit.75 NSAIDS are not protective.76

Glutamine: Effective in some animal studies66,67 but not in others.68,69 Not effective in clinical studies.70

Sulfasalazine and related compounds: Sulfasalazine may be moderately effective.77 Salicylic acid derivatives (5-ASA, etc) are ineffective and possibly even harmful.78-82 Octreotide: Reduces early and chronic radiation enteropathy in animals.83,84 Antitumor and antiangiogenic effects.85,88

Short chain fatty acids (SCFA): Non-controlled clinical studies suggest efficacy.71-74

cers and pain. Omeprazole reduced erosions, but ranitidine did not. Given the relative inexpense of these two drugs, it is reasonable to use them for prophylaxis in patients receiving CMF or 5-fluorouracil. Although they have not been tested against other chemotherapy drugs, it is probably reasonable to extrapolate their use to any regimen likely to cause esophageal and abdominal symptoms. Stomach There is very little research published in this area and there is ample room for further investigation of the gastric response to chemotherapy. From Sartori’s work,89,90 it would seem reasonable to use H-2 blockers or proton pump inhibitors. Small Intestine It is known that cytotoxic agents act at different levels of the small intestinal crypt cell hierarchy.91-94 In general, there are three main classifications of cytotoxic agents: class 1 act at cell positions 4 to 6 and includes bleomycin, class 2 act at cell positions 6 to 8 and includes cyclophosphamide. Class 3 act at cell positions 8 to 11 and includes methotrexate.91-94 However, despite their

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differences in site of action, all of these drugs cause crypt cell apoptosis, followed by crypt hypoplasia and then rebound crypt hyperplasia before returning to normal.1,2,10-12 Although there is always an associated increase in crypt cell apoptosis, this does not necessarily correlate with the severity of overt mucositis,95,96 with recent evidence suggesting an important role is played by the two transcription factors, p53 and p21.95-98 Mucositis is usually more prominent in the small intestine than the colon. This apparent difference in regions has led to new directions in mucositis research, with differences now thought to be related to the change in ratio between the pro- and anti-apoptotic protein expression within the different regions of the GIT. It is well known that the Bcl-2 family of proteins play a fundamental role in cell survival.99,100 Recent research has clearly shown that the small and large intestines have differential expression of pro- and anti-apoptotic Bcl-2 proteins and this contributes to the heightened sensitivity of the small intestine to most chemotherapy agents.101,102 In humans, GI symptoms peak at 3 days postchemotherapy and consist of nausea, abdominal pain, bloating, and diarrhea. Oral symptoms (pain and ulceration) peak at day 14. Oral symptoms are approximately twice as common as GI symptoms with symptoms being more common than signs (ie, nausea, vomiting, mouth pain, and ulceration).2 Following chemotherapy, there is an early increase in apoptosis in the crypts of the duodenum, peaking on day 2, and normalizing by day 16. This is followed by a reduction in mitotic count in the crypts, and reduced crypt length, at day 3. These again normalize by day 16. Electron microscopy shows the presence of apoptotic bodies in the epithelial cells, as well as opening of the tight junctions between epithelial cells. Thus, the earliest changes are histologic and have largely resolved by the time symptoms are developing. Functional changes persist the longest.1,2 Colon Past research has focused on small intestinal side effects of many chemotherapeutic agents such as methotrexate.11,12 However, a relatively

new chemotherapeutic agent, irinotecan (CPT 11) causes significant diarrhea and hypothesized severe colonic damage. Irinotecan causes this severe diarrhea in two phases. The early diarrhea is cholinergic in nature, and can be controlled by the use of prophylactic atropine.10 The mechanism of the later diarrhea is not entirely clear, but it has previously been thought to be caused by goblet cell hyperplasia in the colon, rather than to small bowel damage.103 Gibson et al10 have performed studies with irinotecan and have found that while it does cause goblet cell hyperplasia in the colon, it also causes small intestinal changes similar to those induced by methotrexate. Therefore, the diarrhea is probably multifactorial. CPT-11 also increased apoptosis, villus atrophy, and crypt hypoplasia in the small intestine, increased apoptosis, crypt hypoplasia, and mucus secretion in the colon, and produced a dose-dependent increase in diarrhea and mortality. More recently, a study using keratinocyte growth factor as a antimucotoxic agent in irinotecan-induced mucositis has shown keratinocyte growth factor to be effective in reducing mortality and diarrhea, with deaths being caused by duodenal perforation, not to colonic damage (R.J. Gibson, personal communication, 2003). Thus, to date, all cytotoxic agents tested in animal models show damage to the small intestinal crypts, with some also showing damage in the large intestine. However, not all these may translate into clinical significance.

IMPLICATIONS

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NURSING PRACTICE

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s we increase our knowledge of the pathophysiology of mucositis throughout the GIT, it is important for us to accurately document the extent and severity of GIM in our patients. Once the mechanisms have been fully delineated, it will be possible to target therapeutic interventions to these mechanisms. This will enable the development of targeted therapies in supportive care in a similar manner to the targeted therapies used in cancer treatment. However, until that time, it is important to alleviate symptoms wherever possible.

REFERENCES 1. Keefe DM, Goland GJ, Brealey J, et al. Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut 2000;47:632-637.

2. Keefe DMK. The effect of cytotoxic chemotherapy on the mucosa of the small intestine. Adelaide: University of Adelaide, Department of Medicine: 1998.

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