GASTROINTESTINAL CATEGORY

Typhlitis (also called neutropenic enterocolitis) is an inflammation or necrosis of the bowel, usually confined to the cecum, appendix, and terminal ileum, that is seen in immunocompromised patients with profound neutropenia (e.g., patients on chemotherapy for treatment of cancer). The condition appears to be an infectious process that results from an injury to the intestinal mucosa that predisposes the mucosa to bacterial invasion and eventually to the development of full thickness infarction and bowel perforation. Potential mechanisms of injury include chemotherapy-induced mucosal injury, hypoperfusion leading to submucosal ischemia, and growth of abnormal intestinal flora from aggressive antibiotic use. Patients typically present with fever, abdominal pain, and tenderness on physical exam of the abdomen, frequently localized to the right lower quadrant, in the setting of chemotherapy treatment and neutropenia. Patients may also present with lower GI bleeding and watery diarrhea. The diagnosis is usually made on the basis of the clinical history, symptoms, and CT imaging which demonstrates bowel wall thickening and ileus. Most patients are treated successfully using medical management (antibiotics, bowel rest, close observation) with surgical management reserved for patients with evidence of clinical deterioration.  

Colitis is a more general term that refers to inflammation of the entire colon or any part of the colon (e.g., cecum, ascending colon, transverse colon, descending colon, or signmoid colon). It may result from a variety of underlying causes (e.g., Crohn’s disease, inflammatory bowel disease, ulcerative colitis, pseudomembranous colitis).  

Typhlitis should be graded when a patient exhibits the specific clinical condition defined above while colitis should be used to refer to other conditions that result in inflammation of the colon.

 

Cheilitis, inflammation of the lips or of a lip, is an abnormal condition of the lips characterized by scaling of the surface and by the formation of fissures in the corners of the mouth. It is different from oral mucositis.

 

Colitis is a general term that refers to inflammation of the entire colon or any part of the colon (e.g., cecum, ascending colon, transverse colon, descending colon, or signmoid colon). It may result from a variety of underlying causes (e.g.,ulcerative colitis, pseudomembranous colitis, inflammatory bowel disease, Crohn’s disease, radiation injury). 

 

Constipation refers to infrequent or hard stools (i.e., bowel movements) or to the inability to pass a bowel movement easily. Constipation is a relative term. There is wide variability in what is considered normal patterns of bowel movements. While some people may have consistently soft stools, others may have consistently hard or firm stools, but no difficulty in passing them. When the stool is hard, infrequent, and requires significant effort to pass, the person has constipation. Constipation may cause discomfort with passage of stools, and passage of large, wide stools may tear the mucosal membrane of the anus, especially in children, causing bleeding and the possibility of an anal fissure.

Constipation can often be successfully treated with stool softeners, laxatives, and/or diet modifications. In some cases, constipation can be so severe that obstipation (or intestinal obstruction) can result. Obstipation usually requires either manual or surgical evacuation and decompression. Surgical intervention may also be required to treat perforation associated with severe constipation and obstipation.

 

Endoscopy refers to the use of a lighted tube (called an endoscope) linked to a camera/video display to examine the inside of the body (e.g., the esophagus, stomach, colon, ureters). CTCAE often refers to endoscopy but accurate grade assignment requires that if the patient underwent endoscopic examination but also experienced any of the elements in a higher grade, the higher grade must be reported. For example: A patient experienced uteretal obstruction with renal dysfunction and endoscopic intervention. Even though 'endoscope' is not mentioned in Grade 3, and the patient did not require operative intervention, Grade 3 is the appropriate grade because of 'renal dysfunction.'

Example: Renal Dysfunction

 

Enteritis is a general term that refers to inflammation of the intestine, especially the small intestine. It may result from a variety of underlying causes (e.g., Crohn’s disease, radiation injury, infection).

 

Although esophagitis is inflammation of the esophagus, it typically results from gastroesophageal reflux that may be due to prolonged vomiting or an incompetent esophageal sphincter. Mucosal damage is related to the contact time between the esophageal mucosa and gastric contents, as well as the acidity and quantity of gastric secretions, and again is evaluated by invasive diagnostic tests. So stomatitis and esophagitis are quite different. Swallowing resulting from stomatitis of the mouth or pharynx is included in the definitions for grades for stomatitis.

 

Fistula is defined as an abnormal communication between the cavities of two internal structures or between a cavity of an internal structure and the surface of the skin. While every definition of fistula includes the abnormal connection between two potential spaces open to the outside (i.e., basement membrane must be traversed twice), there are too many possible fistulas to list. Therefore, the CTCAE v3.0 requires that the site indicated for a fistula is the site from which the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as Fistula, GI – Esophagus.

 

A GI obstruction is a partial or complete blockage that results in the failure of intestinal contents to pass through the bowel. Obstruction of the bowel can occur either from mechanical causes (e.g., hernia, adhesions, impacted stool, tumor, volvulus or twisting of the bowel on itself), or non-mechanical caused (e.g., adynamic ileus, dynamic ileus). An adynamic ileus refers to obstruction of the intestine due to paralysis of the bowel wall, usually as a result of localized or generalized peritonitis or shock. A dynamic ileus refers to obstruction of the intestine due to spastic contraction of a segment of bowel.  

Although some may use the term 'ileus' in reference to a mechanical obstruction (e.g., gallstone ileus), in the CTCAE v3.0, the Adverse Event (AE) term 'Ileus' in the GASTROINTESTINAL CATEGORY should be used to refer to any non-mechanical obstruction of the intestine (i.e., underlying condition that results in a paralysis or spastic contraction of the bowel wall leading to dysfunction) and the AE term 'Obstruction' in the GASTROINTESTINAL CATEGORY should be used to refer to any mechanical obstruction of the intestine resulting in bowel dysfunction.

 

Infectious lesions of the mouth are graded in CTCAE v3.0 in the INFECTION CATEGORY. Examples:

Herpetic stomatitis is a viral infection of the mouth characterized by ulcers and inflammation. Symptoms include blisters, ulcers in the mouth, and inflamation of the gums. Ulcers may appear on the inside of the cheeks and tongue usually 1 to 5 millimeters in diameter with a grayish-white base and a reddish perimeter. These ulcers are very painful and can cause drooling, difficulty swallowing, and decrease in food intake. Canker sores are different, since they are not caused by the same virus. Herpetic stomatitis is normally diagnosed based on its very typical appearance. Laboratory studies include viral culture and special stains.

Thrush (fungus Candida albicans) causes creamy white lesions, on the tongue or inner cheeks. The lesions can be painful and may bleed. Sometimes the infection may involve the roof of the mouth, gums, tonsils or throat.

 

The terms 'oral mucositis' and 'stomatitis' are often used interchangeably at the clinical level, but do not reflect identical processes. Oral mucositis describes inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation. Mucositis typically manifests as erythema or ulcerations. It may be exacerbated by local factors. Stomatitis refers to any inflammatory condition of oral tissue, including mucosa, dentition/periapices and periodontium. Stomatitis thus includes infections of oral tissues, as well as mucositis as defined above.

In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice. Specific instruments of varying complexity are used to evaluate the observable and functional dimensions of mucositis. In an attempt to simplify reporting, CTCAE provides two site-specific formats for reporting mucositis based either on symptoms of the patient or clinical findings and measurements of the physician.

 

Typhlitis (also called neutropenic enterocolitis) is an inflammation or necrosis of the bowel, usually confined to the cecum, appendix, and terminal ileum, that is seen in immunocompromised patients with profound neutropenia (e.g., patients on chemotherapy for treatment of cancer). The condition appears to be an infectious process that results from an injury to the intestinal mucosa that predisposes the mucosa to bacterial invasion and eventually to the development of full thickness infarction and bowel perforation.  Potential mechanisms of injury include chemotherapy-induced mucosal injury, hypoperfusion leading to submucosal ischemia, and growth of abnormal intestinal flora from aggressive antibiotic use. Patients typically present with fever, abdominal pain, and tenderness on physical exam of the abdomen, frequently localized to the right lower quadrant, in the setting of chemotherapy treatment and neutropenia. Patients may also present with lower GI bleeding and watery diarrhea. The diagnosis is usually made on the basis of the clinical history, symptoms, and CT imaging which demonstrates bowel wall thickening and ileus. Most patients are treated successfully using medical management (antibiotics, bowel rest, close observation) with surgical management reserved for patients with evidence of clinical deterioration. 

 

Several options included in the GASTROINTESTINAL CATEGORY are loco-regional and are organized using the Supra-ordinate format, including:

Fistula, GI – Select

Leak (including anastomotic), GI – Select

Mucositis/stomatitis (clinical exam) – Select

Mucositis/stomatitis (functional/symptomatic) – Select

Necrosis, GI – Select

Obstruction, GI – Select

Perforation, GI – Select

Stricture/stenosis (including anastomotic), GI – Select

Ulcer, GI – Select

 

Anorexia	No change
Ascites (non-malignant)	No change
Colitis	Grade 1 added
Constipation	No change
Dehydration	No change
Dental: dentures or prosthesis	New AE
Dental: periodontal disease	New AE
Dental: teeth development	New AE
Diarrhea	New AE
Diarrhea patients without colostomy	Merged into v3.0 Diarrhea; Grades 1-4 revised
Diarrhea patients with a colostomy	Merged into v3.0 Diarrhea; Grades 1-4 revised
Diarrhea associated with graft versus host disease (GVHD) for BMT studies, if specified in the protocol	Deleted
Diarrhea For pediatric BMT studies, if specified in the protocol	Deleted
Distension/bloating, abdominal	New AE
Duodenal ulcer (requires radiographic or endoscopic documentation)	Changed to v3.0 ‘Select’ AE under: Ulcer, GI – Select; Grade 1 added; Grades 2-4 revised
Dyspepsia/heartburn	Name revised to Heartburn/dyspepsia
Dysphagia, esophagitis, odynophagia (painful swallowing)	Split to v3.0 Dysphagia (difficulty swallowing) and v3.0 Esophagitis; Grades 1-3 revised for Dysphagia (difficulty swallowing); Grades 1-4 revised for v3.0 Esophagitis
Dysphagia-esophageal related to radiation	Merged into v3.0 Dysphagia (difficulty swallowing); Grades 1-4 revised
Dysphagia-pharyngeal related to radiation	Merged into v3.0 Dysphagia (difficulty swallowing); Grades 1-4 revised
Enteritis (inflammation of the small bowel)	New AE
Fistula, GI – Select	New Supra-ordinate term
Fistula-esophageal:	Changed to v3.0 ‘Select’ AE under: Fistula, GI – Select; Grades 1 and 2 added; Grades 3 and 4 revised
Fistula-intestinal:	Changed to v3.0 ‘Select’ AE under: Fistula, GI – Select Grades 1 and 2 added; Grades 3 and 4 revised
Fistula-pharyngeal:	Changed to v3.0 ‘Select’ AE under: Fistula, GI – Select; Grades 1 and 2 added; Grades 3 and 4 revised
Fistula-rectal/anal	Changed to v3.0 ‘Select’ AE under: Fistula, GI – Select; Grades 1 and 2 added; Grades 3 and 4 revised
Flatulence	No change
Gastric ulcer (requires radiographic or endoscopic documentation)	Changed to v3.0 ‘Select’ AE under: Ulcer, GI – Select; Grade 1 added; Grades 2-4 revised
Gastritis	Name revised to Gastritis (including bile reflux gastritis); Grade 1 added; Grades 2 and 3 revised
Hemorrhoids	New AE
Ileus (or neuroconstipation)	Name revised to Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Grade 1 added; Grades 2-4 revised
Incontinence, anal	New AE
Leak (including anastomotic), GI – Select	New Supra-ordinate term
Malabsorption	New AE
Mouth dryness	Name revised to Dry mouth/salivary gland (xerostomia); Grade 3 added; Grades 1 and 2 revised
Nausea	Grade 4 added; Grades 1-3 revised
Necrosis, GI – Select	New Supra-ordinate term
Obstruction, GI – Select	New Supra-ordinate term
Pancreatitis	Relocated to HEPATOBILIARY/PANCREAS CATEGORY; Grades 1 and 2 added; Grades 3 and 4 revised
Perforation, GI – Select	New Supra-ordinate term
Proctitis	Grades 1-4 revised
Prolapse of stoma, GI	New AE
Salivary gland changes	Name revised to Salivary gland changes/saliva; Grade 3 added; Grade 4 revised
Stricture/stenosis (including anastomotic), GI – Select	New Supra-ordinate term
Sense of smell	Changed to v3.0 ‘Select’ AE under: Neuropathy: cranial – Select; Relocated to NEUROLOGY CATEGORY; Grades 3 and 4 added; Grades 1 and 2 revised
Stomatitis/pharyngitis (oral/ pharyngeal mucositis)	Split into supra-ordinate terms v3.0 Mucositis/stomatitis (clinical exam) – Select and v3.0 Mucositis/stomatitis (functional/ symptomatic) – Select; Grades 1-4 revised; Alternate Grading Criteria Grades 1-3 added for Lower GI Sites
Stomatitis/pharyngitis (oral/ pharyngeal mucositis) for BMT studies, if specified in the protocol	Merged into supra-ordinate terms v3.0 Mucositis/stomatitis (clinical exam) – Select and v3.0 Mucositis/stomatitis (functional/ symptomatic) – Select; Grades 1-4 revised
Mucositis due to radiation	Merged into supra-ordinate terms v3.0 Mucositis/stomatitis (clinical exam) – Select and v3.0 Mucositis/stomatitis (functional/ symptomatic) – Select; Grades 1-4 revised
Taste disturbance (dysgeusia)	Name revised to Taste alteration (dysgeusia); Grade 2 revised
Typhlitis (inflammation of the cecum)	Name revised to Typhlitis (cecal inflammation); Grades 1 and 2 added
Ulcer, GI – Select	New Supra-ordinate term
Vomiting	No change
Gastrointestinal – Other (Specify, ___)	No change