Introduction

Gastrointestinal (GI) toxicities are common side effects of most chemotherapy agents. Their effect on rapidly dividing GI tract cells can lead to mucosal inflammation, ulceration, and perforation. The most common GI toxicities include oral mucositis (see Chapter 5 ), dysphagia, odynophagia, esophagitis, gastritis, nausea and vomiting, enterocolitis, diarrhea, constipation, and hepatotoxicity. Other less common manifestations include GI hemorrhage, bowel perforation, pancreatitis, malabsorption, and infections of the GI tract as a result of chemotherapy-induced immunosuppression. This chapter highlights the mechanisms of chemotherapy-induced GI toxicities and important pharmacological and nonpharmacological management strategies.

Esophageal Complications of Chemotherapy

Clinical esophagitis is observed in 1% to 3% of cancer patients undergoing anticancer treatment and is most commonly due to direct toxicity of chemotherapy or radiation therapy. Patients who are on corticosteroids or are immunosuppressed may develop esophagitis caused by a bacterial, fungal, or viral infection. Candida species, herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella zoster virus (VZV) comprise the majority of pathogens. Gastric acid suppressants (e.g., proton pump inhibitors) can contribute to fungal and bacterial colonization of the upper GI tract, predisposing to infectious esophagitis. Other risk factors include gastroesophageal reflux disease (GERD) and pill-induced esophagitis.

Chemotherapy implicated in esophagitis: A number of chemotherapy agents, including doxorubicin, vinblastine, 5-fluorouracil (5-FU), methotrexate, and dactinomycin, have been associated with esophagitis. However, the incidence of chemotherapy-induced esophagitis is low and is more commonly observed in combination with thoracic radiation therapy. The pathophysiology of esophagitis due to concurrent chemoradiotherapy is complex and multifactorial, but is believed to involve direct cytotoxic injury followed by secondary insult due to the release of proinflammatory cytokines. Agents such as cyclophosphamide, 5-FU, doxorubicin, and dactinomycin also act as radiosensitizers and can exacerbate the cytotoxic effects of radiation.

Esophagitis frequently presents with retrosternal burning, dysphagia, and odynophagia. Subsequent reduced oral intake can lead to dehydration, weakness, need for alternate feeding routes, and treatment interruption. A grading system for esophagitis is described in Table 6.1 .

Management of esophagitis: Management depends on the degree of clinical impact, etiology, and other patient-related factors. Most cases are treated with conservative measures such as hydration; soft, bland diet; and adequate pain control. Patients should be instructed to avoid hot beverages, spicy foods, citrus, alcohol, and tobacco. Use of antacid therapy such as proton pump inhibitors, topical lidocaine, or topical soothing agents such as “Magic Mouthwash” is also recommended before meals to facilitate swallowing. Sucralfate can be used as an adjunct medication in the treatment of pill-induced esophagitis because it can hasten the healing rate by adhering to esophageal ulcers. More severe cases may require switching to a liquid diet with high-calorie supplements for nutritional support, and analgesics such as narcotics. Hospitalization may be necessary to provide nutrition via the percutaneous or parenteral route in these cases. Endoscopic evaluation is not commonly indicated and can be complicated by perforation. However, endoscopy may be therapeutic in patients with known or suspected esophageal strictures because the surgical dilation of esophageal strictures is usually associated with excellent results, and can be diagnostic in providing etiology of infectious esophagitis.

Evaluation of esophagitis: Workup of a patient with suspected esophagitis should include a good oral examination and consideration for a smear and culture of oral mucosa for Candida . Candidal infection is more common in immunocompromised patients and may or may not be associated with oropharyngeal thrush. The hallmark of esophageal candidiasis is odynophagia, although many patients may be asymptomatic. Treatment involves azole derivatives, such as fluconazole. If definitive diagnosis is not possible or inconclusive, empiric antifungal therapy should be considered due to the risk of esophageal mucosa sloughing and stricture or fistulae formation.

Viral esophagitis: HSV esophagitis usually arises from reactivation of latent virus during treatment-induced immunosuppression. Patients with oral lesions suggestive for HSV infection along with dysphagia or odynophagia are likely to have HSV esophagitis, and culture and histological examination of the oral mucosa are recommended. The treatment of choice is acyclovir. For patients who are able to take oral medications, acyclovir 400 mg PO 5 times a day for 14 to 21 days is effective. For patients who cannot tolerate oral therapy, intravenous acyclovir can be given 5 mg/kg every 8 hours for 7 to 14 days and as soon as their symptoms improve, they can be switched to oral therapy for completion of the therapeutic course. Foscarnet can be used with caution in patients with acyclovir resistance.

Chemotherapy-Induced Nausea and Vomiting

Chemotherapy-induced nausea and vomiting (CINV) remains one of the most distressing and dreaded adverse events associated with chemotherapy. Up to 80% of patients receiving chemotherapy have CINV; however, the incidence and severity depend on the chemotherapy regimen, dosage, duration, and patient risk factors. CINV has been associated with poor adherence to chemotherapy, disruption of treatment schedules, impairment of functional activity, and significant negative impact on quality of life. Uncontrolled or poorly controlled CINV is associated with dehydration, metabolic imbalances, malnutrition, and weight loss leading to frequent hospitalizations and increased use of healthcare resources. Early prevention and active management are essential to reduce the incidence and consequences of CINV and enhance the care of cancer patients.

Significant progress has been made in our understanding of the pathophysiology of CINV, facilitating the development of effective targeted pharmacotherapies including 5-hydroxytryptamine-3 (5-HT3) receptor antagonists and neurokinin-1 (NK-1) receptor antagonists. As many as 70% to 80% of CINV cases can be prevented with appropriate administration of evidence-based antiemetic regimens.

Classification of Chemotherapy-Induced Nausea and Vomiting

CINV is classified into three major categories according to the time of onset: acute, delayed, and anticipatory. In addition, two further categories describe uncontrolled symptoms: breakthrough and refractory CINV.

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  Acute emesis occurs within 24 hours of initial administration of chemotherapy with a peak incidence seen at 4 to 6 hours.

  
  
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  Delayed emesis occurs more than 24 hours to several days after the initial administration of chemotherapy with a peak incidence at 2 to 3 days. Delayed CINV is typically associated with cisplatin; however, the phenomenon has also been noted with cyclophosphamide, carboplatin, doxorubicin, and ifosfamide administration at higher doses.

  
  
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  Anticipatory emesis precedes drug administration and is believed to be a conditioned response in patients who have experienced significant CINV during previous cycles of treatment. Common triggers for anticipatory CINV include the environment (physician’s office or infusion room), foods, smells, or even cognitive stimuli.

  
  
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  Breakthrough CINV is nausea and/or vomiting occurring within 120 hours of chemotherapy administration, despite optimal antiemetic prophylaxis based on CINV guidelines. The incidence of breakthrough CINV is 30% to 50% in patients receiving chemotherapy.

  
  
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  Refractory CINV is the failure to respond to guideline-directed prophylactic antiemetic agents during a previous cycle of treatment, with nausea and vomiting occurring in subsequent chemotherapy cycles.

Risk Factors for the Development of Chemotherapy-Induced Nausea and Vomiting

There are multiple risk factors for the development of CINV. Younger and female patients both have an increased risk of more frequent and severe CINV, whereas patients who are older, male, and those with a history of chronic alcohol consumption tend to be less affected by CINV. Patients with a history of motion sickness and/or pregnancy-related nausea and vomiting have a higher risk of developing CINV. The emetogenicity of the chemotherapeutic agent is the single most important risk factor for development of CINV and is the major criterion for determining the optimal antiemetic prophylaxis regimen. Emetogenicity is a measure of how likely a chemotherapy agent is to cause emesis without antiemetic premedication.

Antineoplastic agents are classified as:

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  highly emetogenic (>90% of patients experience CINV)

  
  
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  moderately emetogenic (30%–90% of patients experience CINV)

  
  
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  lowly emetogenic (10%–30% of patients experience CINV)

  
  
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  minimally emetogenic (<10% of patients experience CINV)

Table 6.2 lists important IV and oral chemotherapeutic agents by emetic risk. For certain agents such as cyclophosphamide and doxorubicin, emetogenicity depends on the dose. The risk of developing CINV can also be influenced by the route and frequency of chemotherapy administration. For combination regimens, emetogenic levels are determined by identifying the most emetogenic agent in the combination and then assessing the relative contribution of the other agents.

Pathophysiology of Chemotherapy-Induced Nausea and Vomiting

The pathophysiology of CINV is complex and multifactorial. It involves multiple neurotransmitters, neuroreceptors, and neuronal pathways in the central nervous system (CNS) and peripheral structures. The three main neurotransmitters are serotonin, substance P, and dopamine and the receptors associated with them are 5-HT3, NK-1, and dopamine-2 (D2) receptors, respectively. Other receptors involved include corticosteroid, histamine, cannabinoid, acetylcholine, and opiate receptors, although their roles are not precisely defined.

CINV mainly occurs via activation of peripheral and central pathways. The peripheral pathway is mediated via binding of serotonin to 5-HT3 receptors located in the GI tract and is activated within the first 24 hours after chemotherapy administration; it is primarily associated with acute emesis. The central pathway is activated via binding of substance P to NK-1 receptors in the brain and is thought to be predominantly involved in delayed CINV. A simplified illustration of the pathways involved in the pathophysiology of CINV has been depicted in Fig. 6.1 . Chemotherapy can stimulate the enterochromaffin cells lining the digestive tract to release serotonin in response to cell damage. Serotonin binds to 5-HT3 receptors on the nearby vagal afferents in the gut, which in turn causes the transmission of sensory input from the GI tract to the vomiting center in the brain, located in the dorsolateral border of medulla. The vomiting center receives signals from other structures, including the chemotherapy trigger zone (CTZ) in the area postrema, which is lined by 5-HT3 and D2 receptors. Chemotherapy can directly activate the CTZ chemoreceptors because they lack an effective blood–brain barrier. All the sensory signals are consolidated in the vomiting center, resulting in the generation of efferent signals that lead to contraction of the abdominal muscles, the stomach, and the diaphragm, causing subsequent emesis. Each of these neurotransmitters and their corresponding receptors are of primary interest and therapeutic targets for development of antiemetic drugs.

Pathophysiology of chemotherapy induced nausea and vomiting. 5-HT , 5-Hydroxytryptamine; CTZ , chemoreceptor trigger zone; D2 , dopamine-type 2; H1 , histamine 1; M , muscarinic; NTS , nucleus tractus solitarii; SP , substance P; VC , vomiting center.

Management and Prevention of Chemotherapy-Induced Nausea and Vomiting

Antiemetic Regimens Based on Emetogenicity of Chemotherapy

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  Antiemetic regimens for highly emetogenic chemotherapy: Patients treated with cisplatin or other highly emetogenic single chemotherapeutic agents should be offered a four-drug combination of a NK1 receptor antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine on day 1 of treatment. Dexamethasone and olanzapine are recommended to be continued on days 2 to 4 ( Table 6.3 ). Alternatively, three-drug regimens including single doses of a 5-HT3 receptor antagonist, dexamethasone, and an NK1 receptor antagonist can also be given for prevention of CINV for HEC. For patients receiving anthracycline/cyclophosphamide (AC) combination chemotherapy, a four-drug combination of NK-1 receptor antagonist, 5-HT receptor antagonist, dexamethasone, and olanzapine is recommended prior to the start of cytotoxic treatment (day 1) and only olanzapine is continued on days 2 to 4. Dexamethasone is not recommended on days 2 to 4 due to limited data supporting its benefit beyond day 1. Alternatively, a three-drug regimen including single doses of a 5-HT3 receptor antagonist, dexamethasone, and an NK1 receptor antagonist can also be given for prevention of CINV in patients receiving AC combination chemotherapy.

  
  
  
  

  TABLE 6.3■

  
  

  Antiemetic Dosing for Adults Receiving Chemotherapy

  
  

  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

  Regimen	Drugs	Dose on Day 1	Dose on Days 2, 3, 4
  Highly Emetogenic Chemotherapy
  4-Drug combination regimen (NK-1 RA, 5-HT3 RA, dexamethasone, olanzapine)	NK-1 RA (choose one): Aprepitant Fosaprepitant Rolapitant NEPA	125 mg PO 150 mg IV once 180 mg PO once (300 mg netupitant/0.5 mg palonosetron PO combination) once	80 mg oral on days 2, 3
  	5-HT3 RA (choose one): Granisetron Ondansetron Palonosetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg sc 8 mg PO twice daily or 8 mg or 0.15 mg/kg IV once 0.50 mg oral or 0.25 mg IV once
  	Dexamethasone	12 mg PO/IV once	8 mg PO/IV daily on days 2, 3, 4
  	Olanzapine	10 mg PO	10 mg PO daily on days 2, 3, 4
  3-Drug NK-1 RA based combination regimen	NK-1 RA (choose one): Aprepitant Fosaprepitant Rolapitant NEPA	125 mg PO once 150 mg IV once 180 mg PO once (300 mg netupitant/0.5 mg palonosetron PO combination) once	80 mg PO daily on days 2, 3
  	5-HT3 RA (choose one): Granisetron Ondansetron Palonosetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg sc 8 mg PO twice daily or 8 mg or 0.15 mg/kg IV once 0.50 mg oral or 0.25 mg IV once
  	Dexamethasone	12 mg PO/IV once	8 mg PO/IV daily on days 2, 3, 4
  Moderately Emetogenic Chemotherapy
  Carboplatin based: 3-drug combination regimen (NK-1 RA + 5-HT3 RA + dexamethasone)	NK-1 RA (choose one): Aprepitant Fosaprepitant Rolapitant NEPA	125 mg PO 150 mg IV once 180 mg PO once (300 mg netupitant/0.5 mg palonosetron PO combination) once	80 mg PO daily on days 2, 3
  	5-HT3 RA (choose one): Granisetron Ondansetron Palonosetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg sc 8 mg PO twice daily or 8 mg or 0.15 mg/kg IV once 0.50 mg oral or 0.25 mg IV once
  	Dexamethasone	12 mg PO/IV once
  Non-carboplatin based: 2-drug combination regimen (5-HT3 RA + dexamethasone)	5-HT3 RA (choose one): Granisetron Ondansetron Palonosetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg sc 8 mg PO twice daily or 8 mg or 0.15 mg/kg IV once 0.25 mg IV once
  	Dexamethasone	8 mg PO/IV once	8 mg PO/IV on day 3
  Low Emetogenic Chemotherapy
  Single agent dexamethasone	Dexamethasone	8 mg PO/IV once
  Single agent 5-HT3 RA	5-HT3 RA (choose one): Granisetron Ondansetron Palonosetron	2 mg PO or 1 mg or 0.01 mg/kg IV or 1 transdermal patch or 10 mg sc 8 mg PO twice daily or 8 mg or 0.15 mg/kg IV once 0.25 mg IV once
  Single agent dopamine RA	Dopamine RA (choose one): Metoclopramide Prochlorperazine	10–20 mg PO/IV once 10 mg PO/IV once
  Minimally Emetogenic Chemotherapy
  No routine prophylactic antiemetics

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