Definition/Diagnosis

Oral and gastrointestinal mucositis is an inflammation of the mucous membranes [1] and is a result of biological events involving the epithelium and submucosa induced by chemotherapy and radiotherapy [2]. Mucositis is a significant source of pain for many patients, and is thus of clinical relevance as it poses as a dose- and treatment-limiting side effect when it begins to interfere considerably with a patient’s quality of life (QOL) [1]. As a result of its interference with cancer therapy, mucositis can potentially impact tumor response and long-term patient survival [3].

Oral mucositis primarily affects the soft palate, floor of the mouth, buccal mucosa, lateral margins, and ventral surface of the tongue and lips [2]. It is characterized by inflammation of the mucous membranes of the oral cavity and oropharynx and is distinguished by erythema, edema, atrophy, and often ulceration [1]. The World Health Organization (WHO) grades the severity of oral mucositis on a 0–4 grade point scale. Another research-based scale is the Oral Mucositis Assessment Scale (OMAS), which shows a strong correlation with more global scales such as the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) instrument. Table 7.1 summarizes the WHO measure.

Esophagitis is similar to mucositis both in presentation and management [4]. Symptoms of esophagitis include the onset of retrosternal chest pain and odynophagia [5]. Other symptoms that may aid in differential diagnosis include candidiasis, HSV, CMV, bacterial infections, and aspergillosis [5]. Chemotherapy (CT) and radiotherapy (RT)-induced esophagitis may produce an erosive esophagus that is clinically indistinguishable from infection—diagnosis of which requires an endoscopy or biopsy [5].

Prevalence/Progression

Treatment

Esophagitis

The literature on the management for esophagitis is scarce; thus, institutional protocols have been developed [6]. The management of esophagitis has been described as being similar to mucositis [4] and is mainly supportive—often requiring dietary changes, topical agents, and narcotic pain medication [6]. Several suggestions for management of symptoms have been proposed and are listed in Table 7.5.

Definition/Diagnosis

Diarrhea is defined as the urgent and frequent passage of loose or watery stools [8,9]. More specifically, some define diarrhea as the passage of three or more loose stools per day [9]. Another definition characterizes diarrhea as passing ≥200 g of stool per day based on a typical diet [9]. As in the case of constipation, however, a patient's perspective of diarrhea will vary and should be further clarified by health care providers. The grading of severity of diarrhea, as outlined by the National Cancer Institute, is displayed in Table 7.6.

Severe diarrhea can lead to dehydration, malnutrition, electrolyte imbalance, pressure ulcer formation, and weakening of the immune function [8]. It is debilitating and may, in some cases, even be life-threatening [8].

Presentation/Prevalence/Progression

Diarrhea is a well-known adverse effect resulting from abdominal or pelvic RT [11]. Radiation treatment often results in injury to the lower intestine and damages intestinal mucosa; consequent prostaglandin release and bile salt malabsorption together stimulate increased intestinal peristalsis, resulting in diarrhea [8]. Moreover, radiotherapy to the abdominal region may disturb the colonization resistance of the gut flora, causing enteritis—an inflammation of the gastrointestinal tract that leads to severe diarrhea [12]. Approximately 50% of patients treated by pelvic and abdominal RT experience diarrhea and abdominal cramping as a result of acute enteritis [11].

Symptoms of RT-induced diarrhea usually occur during the third week of fractionated RT [11]. Enteritis is often accompanied by proctitis, an inflammation of the anus and rectum and acute radiation enteritis/proctitis occur within approximately 6 weeks of therapy [8]. Late radiation enteritis/proctitis occurs around 8–12 months after RT and may be delayed for years [8]. Onset of these late symptoms may manifest in the form of malabsorption and/or diarrhea [8].

Treatment

Standard therapy for diarrhea consists of oral opiates such as loperamide and diphenoxylate, which are effective in most patients with mild symptoms. However, a randomized trial published in 2000 showed octreotide (100 μg tid) to be significantly more effective than oral diphenoxylate (10 mg/day), with 61% of patients on octreotide resolved of diarrhea in three days versus only 14% of the patients treated with diphenoxylate [11,13].

RT-induced diarrhea requires a therapy procedure that differs from treatments designed to manage diarrhea arising from other causes [11]. Guidelines for management of cancer treatment-induced diarrhea published in 2004 by the American Society for Clinical Oncology recommends a procedure to specifically manage RT-induced diarrhea [11]. We summarize the treatment procedure for managing mild to moderate RT-induced diarrhea in Fig. 7.1. A sample treatment might be: Loperamide (4 mg PO first then 2 mg following each episode of diarrhea up to max of 16 mg a day) and ensuring adequate hydration.

The procedure outlined in Fig. 7.1 concerns cases of mild to moderate diarrhea. In cases in which mild to moderate diarrhea involves moderate to severe cramping, nausea and vomiting, diminished performance status, fever, sepsis, neutropenia, bleeding, or dehydration, and in cases of severe diarrhea, patients are classified as “complicated” [8].

In cases of complicated RT-induced diarrhea, patients require intensive monitoring and management in hospitals, intensive home care nursing programs, or adequate outpatient facilities that are capable of providing the level of care necessary [8]. In addition, these patients should undergo complete stool and blood workup and should be treated with octreotide in conjunction with intravenous antibiotics [8]. In most RT-induced diarrhea cases, however, it may be inappropriate to prescribe octreotide and a complete stool and blood workup may be unnecessary.

There have been several clinical trials which have focused on the prevention of diarrhea in patients undergoing pelvic RT [12]. The results of these studies are summarized in Table 7.7.

Definition/Diagnosis

Constipation is the slow passage of feces through the large intestine that results in infrequent bowel movements [8]. In the case that a bowel movement does occur, the stool is dry and hard [8]. Constipation is defined under the Rome III criteria with an emphasis on the physical characteristics of the stool, the frequency of bowel movements, and other subjective measures of distress to the patient [9]. The criteria for functional constipation are presented in Table 7.8.

While guidelines have been laid out by the Rome III criteria, it is important to note that people differ with respect to the weights that they attribute to different aspects of this symptom cluster and patients may often consider themselves constipated even when they do not qualify as being constipated under the Rome III criteria [19]. As such, a diagnosis of constipation should primarily focus on a patient's complaint of the problem, and focus on his or her account of the situation [19]. Patients’ assessment of their constipation can be assessed visually or with the aid of questionnaires and adjective scales [19]. Table 7.9 summarizes several formal methods of assessment.

Presentation/Prevalence

The presentation of constipation in patients as a direct adverse effect of radiation treatment is not well-documented. Constipation is often the result of a combination of factors rather than a single one [20]. Unlike the prevalence of diarrhea as an adverse result of radiation treatment, constipation is more often a result of chemotherapy regimens involving platinum compounds, vinca alkaloids, taxanes, thalidomide, bortezomib, and 5-HT₃ antagonist antiemetics, as well as opioid usage for the control of pain [8,9,19]. While a causative relationship between radiation and subsequent constipation is not often iterated, it has been noted as a possible side effect of radiation [21] and around 50% of patients admitted to a hospice report constipation [19]. In fact, constipation is often a more common problem than diarrhea in patients with advanced cancer as a result of the wide use of opioid analgesics for pain management [8]. As such, we nevertheless proceed to discuss methods in treating constipation.

Treatment

Treatment of constipation is predominantly characterized by the use of laxative agents classified into two classes: (1) stool softening laxatives and (2) peristalsis-stimulating laxatives [19]. Constipation of increasing severity often responds best to a combination of these two types. Stool softening and peristalsis-stimulating laxatives are listed in Tables 7.10 and 7.11, respectively. A sample regimen would include: prune juice and stool softener (docusate 100 mg BID) and Senna; if no improvement is observed in 3 days, consider prescribing milk of magnesia, Ex-Lax, or MiraLax. If still no improvement: magnesium citrate or lactulose (30 cc po qd) may be initiated, and then fleets enema.

In the case that oral laxatives prove inadequate, rectal laxatives can attempt to aid in ameliorating the situation. Table 7.12 lists several rectal interventions available.

Moreover, it is important to note that constipation is the most frequent and persistent side effect of opioid treatment. Thus, cancer patients undergoing radiation who are on opioids may experience exacerbated effects of constipation. Such patients on narcotic pain regimens should have an accompanying bowel regimen as well.

Incidence

Radiation-induced nausea and vomiting (RINV) is one of the most characteristic adverse effects of radiation therapy and is often the first clear indication of radiation toxicity [22]. However, RINV continues to be underestimated by radiation oncologists [23] despite its clinically significant outcome of potentially decreasing compliance with treatment [24]. If deprived of prophylactic treatment, approximately 50–80% of patients undergoing RT will experience such symptoms [23]. In a study of 1020 patients receiving RT conducted by Maranzano et al. in 2010, nausea and vomiting were reported by 28%, with a median time of 3 days until the first episode of vomiting [25]. Seventeen percent of patients in the study were given antiemetic drugs, with 12% given prophylactic treatment and 5% given rescue therapy. A second cohort of patients studied by Enblom et al. in 2009 showed higher incidence rates for nausea and vomiting, at 39% of patients [26].

Risk Factors

Guidelines for categorizing the risk of emesis due to RT are divided into four categories by the Multinational Association for Supportive Care in Cancer (MASCC) and the European Society for Medical Oncology (ESMO). These guidelines have been endorsed by the American Society of Clinical Oncology (ASCO) [27]. We summarize these categories in Table 7.13.

Treatment

The 5-HT₃ receptor antagonists are the first class of antiemetic drug design specifically as prevention against radiation-induced emesis [28]. There is a biological basis for the effectiveness of this class of drugs. Specifically, animal models have aided in providing insight into the pathophysiology of emesis and have helped illuminate the mechanism with which they act to prevent RINV [29]. 5-HT₃ receptor antagonists inhibit emesis by blocking the action of 5-HT at the site of 5-HT₃ receptors on the vagus nerve in the gastrointestinal tract and in the hindbrain vomiting system [29]. These drugs are useful in both prophylactic and rescue settings. Breakthrough RINV is vomiting and/or nausea occurring within 5 days of radiation after the use of guideline-directed prophylactic antiemetic agents (agents used to prevent RINV). This type of RINV usually requires immediate “rescue” with additional antiemetics. The efficacy of 5-HT₃ receptor antagonists have been confirmed in many trials and the standard guidelines for antiemetic dosing by radiation risk group are now available. Namely, the American Society of Clinical Oncology recently released a practice guideline update for antiemetics that was published in 2011. A summary of their recommendations is reproduced in Table 7.14. A sample regimen might be as follows: Start on ondansetron 8 mg PO an hour prior to radiotherapy, and escalate to three times a day if needed. If this is ineffective, prochlorperazine (5–10 mg PO q 8 h PRN) or metoclopramide (5–10 mg PO q 8 h) may be added. For RINV prophylaxis, we recommend prophylactic administration of ondansetron 8 mg PO 1 hour prior to radiotherapy treatment.