N. Chiu1, N. Pulenzas1, E. Maranzano2, C. DeAngelis1, N. Zhang3, H.-H.M. Yu4 and E. Chow1, 1University of Toronto Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, 2Santa Maria Hospital, Terni, Italy, 3Liaoning Cancer Hospital & Institute, Cancer Hospital of China Medical University, Liaoning, China, 4H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
Radiation is a common and effective treatment for a variety of tumors. Despite its benefits, however, radiation is known to induce several adverse effects in patients that may negatively impact their quality of life and be dose-limiting. The following chapter discusses several such effects, including: mucositis, esophagitis, diarrhea, constipation, as well as nausea and vomiting. This chapter is intended as a quick guide for physicians to refer to; thus, each section will briefly cover the diagnosis, prevalence, and other background information before delving primarily in a discussion of the appropriate treatment options available.
Radiation-induced; mucositis; esophagitis; constipation; diarrhea; nausea and vomiting
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.
Table 7.1
World Health Organization (WHO) Scale
Source: Taken from Davis MP, Feyer P, Ortner P, Zimmermann C. Chapter 11, Oral and gastrointestinal mucosal adverse effects. Supportive Oncology. Philadelphia: Elsevier Saunders; 2011. p. 102–113.
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].
Eighty-five percent of patients undergoing RT for primary tumors of the oral cavity, oropharynx, or nasopharynx experience WHO grade 3 or 4 oral and/or oropharyngeal mucositis [3]. In another study of 75 patients receiving RT for head and neck cancer, 76% experienced severe oral pain, 51% required a feeding tube, and 37% were hospitalized for an average of 4.9 days [1].
The severity of the mucositis is governed mainly by the dosimetry of radiation to mucosal tissue. The risk factors corresponding to radiation dosimetry and the clinical progression of RT-induced mucositis are presented in Tables 7.2 and 7.3, respectively.
Acute esophagitis occurs usually in week 3–4 of conventionally fractionated radiotherapy [6]. Patients with acute esophagitis will experience dysphagia, odynophagia, and heartburn; if not treated early, patients will experience weight loss and dehydration.
Due to the challenging nature of mucositis treatment and the associated costs of managing the effects, the Mucositis Study Group of the Multinational Association for Supportive Care in Cancer and the International Society of Oral Oncology (MASCC/ISOO) saw the need for an evidence-based literature review to produce guidelines for mucositis management [7]. The guidelines were updated in 2007 and the guidelines for prevention and treatment of radiotherapy-induced mucositis are reproduced in Table 7.4.
Table 7.4
MASCC/ISOO Summary of Evidence-Based Clinical Practice Guidelines for Care of Patients With Oral and Gastrointestinal Mucositis
Source: Taken from Keefe DM, et al. Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 2007; 109(5): 820–831.
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.
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.
Table 7.6
Common Toxicity Criteria (version 4.0) for Diarrhea
Grade | Description |
1 | An increase of <4 stools/day over baseline; mild increase in ostomy output compared to baseline |
2 | An increase of 4–6 stools/day over baseline; moderate increase in ostomy output compared to baseline |
3 | An increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care ADL |
4 | Life-threatening consequences; urgent intervention indicated |
Death |
Source: Adapted from National Cancer Institute. Common terminology criteria for adverse events (CTCAE). US Department of Health and Human Services, National Cancer Institute; 2010 [10].
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].
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].
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.
Table 7.7
Clinical Trial Findings on Preventative Measures Against Diarrhea in Patients Undergoing Pelvic RT
Treatment | Clinical Trial Finding | |
Sucralfate | ✓ 3 European trials: Significant decline in occurrence of diarrhea in patients treated with 1–2 g of sucralfate 2–6 times daily when compared with placebo [13–15] ✓ Swedish trial: Significant decline in long-term bowel dysfunction in patients treated with sucralfate ✓ NCCTG trial and Australian trial: No improvement in diarrhea and significant worsening of some GI symptoms when compared with placebo group [16,17] | |
Salicylates | Sulfasalazine | |
Olsalazine | ✓ Turkish study: Increased diarrhea dramatically when compared with placebo [18] |
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.
Table 7.8
Rome III Criteria for Functional Constipation
Source: Adapted from Cherny NI, Werman B. Diarrhea and constipation. In: DeVita VT, Lawrence TS, Rosenberg SA, editors. Cancer principles & practice of oncology. 10th ed. Philadelphia: Wolters Kluwer Health; 2015.
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.
Table 7.9
Formal Methods of Assessment for Constipation
Source: Information obtained from Davis MP, Feyer PC, Ortner P, Zimmermann C. Chapter 11, Oral and gastrointestinal mucosal adverse effects. Supportive oncology. Philadelphia: Elsevier Saunders; 2011. p. 102–113.
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 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.
Table 7.10
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.
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].
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.
Table 7.13
Emetic Risk Categories of Radiation
Emetic Risk | Risk of Emesis Without Antiemetic Prophylaxis (%) | Irradiated Area |
High | >90 | Total body irradiation (TBI), Total nodal irradiation (TNI) |
Moderate | 60–90 | Upper abdominal irradiation, hemibody irradiation (HBI) and upper body irradiation (UBI) |
Low | 30–60 | Cranium (all), craniospinal, head and neck, lower thorax region, pelvis |
Minimal | <30 | Breast and extremities |
Source: Taken from Feyer P, et al. Radiation induced nausea and vomiting. Eur J Pharmacol 2014; 722:165–171.
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.
Table 7.14
Antiemetic Dosing by Radiation Risk Category
Dose | Schedule | ||
High Emetic Risk | |||
5-HT3 antagonist | Granisetrona | 2 mg oral | 5-HT3 antagonist before each fraction throughout XRT. Continue for at least 24 hours following completion of XRT |
1 mg or 0.01 mg/kg IV | |||
Ondansetrona | 8 mg oral twice daily | ||
8 mg or 0.15 mg/kg IV | |||
Palonosetronb | 0.50 mg oral | ||
0.25 mg IV | |||
Dolasetron | 100 mg oral ONLY | ||
Tropisetron | 5 mg oral or IV | ||
Corticosteroid | Dexamethasone | 4 mg oral or IV | Before fractions 1–5 |
Moderate Emetic Risk | |||
5-HT3 Receptor antagonist |
Any of the above listed agents are acceptable, note preferred option b | 5-HT3 antagonist before each fraction throughout XRT | |
Corticosteroid | Dexamethasone | 4 mg IV or oral | Before fractions 1–5 |
Low Emetic Risk | |||
5-HT3 Receptor antagonist |
Any of the above listed agents are acceptable, note preferred options | 5-HT3 either as rescue or prophylaxis. If rescue is utilized, then prophylactic therapy should be given until the end of XRT | |
Minimal Emetic Risk | |||
5-HT3 Receptor antagonist |
Any of the above listed agents are acceptable, note preferred options | Patients should be offered either class as rescue therapy once prior to RT. If rescue is utilized, then prophylactic therapy should be given until the end of XRT | |
Dopamine receptor antagonist |
Metoclopramide | 20 mg oral | |
Prochlorperazine | 10 mg oral or IV |
IV, intravenous; XRT, radiation therapy; bid, twice daily; qid, four times daily; q, every; h, hours.
aPreferred Agents.
bNo data are currently available on the appropriate dosing frequency with palonosetron in this setting. The Update Committee suggests dosing every second or third day may be appropriate for this agent.
Source: Adapted from Basch E, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2011;29(31):4189–4198.