The Gastrointestinal Complications of Oncologic Therapy

A spectrum of oncologic treatments including chemotherapy, radiotherapy, and molecular targeted therapies is available to combat cancer. These treatments are associated with adverse effects in several organ systems including the gastrointestinal (GI) tract. Any part of the GI tract can be affected including the upper GI tract (esophagitis due to bacterial, viral, and fungal infections; mucositis due to chemotherapy or radiation; GI bleeding; nausea and vomiting), colon (diarrhea, graft-vs-host disease [GVHD], and constipation), liver (drug toxicity and GVHD), and pancreas (pancreatitis). Adverse effects range from mild to life threatening. The primary goal of cancer treatment is to administer the most effective therapy while minimizing potential toxicity. This review discusses common GI complications that can result from cancer therapy. The pathologic mechanisms underlying each complication and the pharmacology of the agents used to treat these complications are discussed.

Esophagitis

Esophagitis in patients with cancer may be caused either by the direct cytotoxic effects of chemotherapy or radiation or by the infections caused by immunosuppressive effects of cancer therapy ( Table 1 ). Treatment with chemotherapy or radiotherapy destroys rapidly dividing cells, such as those in the epithelial cell layer. Cell death decreases the renewal rate of the basal epithelium, causing mucosal atrophy, ulceration, and initiation of the inflammatory response. Synergy between chemotherapy and radiotherapy may increase the severity and extent of esophagitis observed with combined therapy. Esophagitis may also be caused by pill-induced injury, acid reflux disease, and GVHD in hematopoietic stem cell transplant recipients.

Table 1

Common causes of esophagitis in patients receiving oncologic therapy

Infectious Agent or Injury	Endoscopic Appearance	Treatment
Candida albicans	White plaquelike lesions with surrounding erythema on the esophageal mucosa	Systemic antifungal treatment with fluconazole, itraconazole, voriconazole, or echinocandins)
Herpes Simplex Virus	Small vesicles, coalescing to form ulcers	Acyclovir, foscarnet sodium
Cytomegalovirus	Linear or serpiginous ulcers	Ganciclovir, foscarnet sodium
Varicella-Zoster Virus	Small vesicles, similar to herpes simplex virus ulcers	Intravenous acyclovir
Polymicrobial Oral Flora	Bacteria mixed with necrotic epithelial cells in biopsy samples	Broad-spectrum antibiotics
Radiation Injury	Friable mucosa with erythema and edema	Lidocaine hydrochloride, proton pump inhibitors, endoscopic dilation, or stents

Data from Davila M, Bresalier RS. Gastrointestinal complications of oncologic therapy. Nat Clin Pract Gastroenterol Hepatol 2008;5(12):682–96.

Fungal Infections

Esophageal candidiasis is common in immunocompromised patients, with Candida albicans being the most frequent causative organism for esophageal and oropharyngeal candidiasis (OPC). Patients complain of odynophagia and/or dysphagia. On endoscopy, esophageal candidiasis is identified by white plaquelike lesions with surrounding erythema. Esophageal biopsies or brushings may confirm the presence of invasive yeast or hyphal forms of C albicans .

An empirical course of antifungal therapy is recommended in immunocompromised patients with odynophagia or dysphagia. Endoscopy should be performed if symptoms do not improve within 72 hours. The general duration of antifungal treatment is 14 to 21 days. Candida esophagitis in immunocompromised patients requires systemic antifungal therapy and cannot be treated with topical agents. Patients unable to tolerate oral agents require intravenous therapy.

The treatment of esophageal candidiasis includes agents such as azoles, echinocandins, or amphotericin B. Azoles inhibit cell membrane formation by inhibiting the synthesis of ergosterol, a principal component of fungal cell membranes. Fluconazole is the recommended first line agent because of its efficacy, ease of administration, and low cost. For patients with fluconazole-refractory esophageal candidiasis who can tolerate oral therapy, newer azoles (voriconazole and posaconazole) are available ( Table 2 ). Itraconazole has been found to be as effective as fluconazole for the treatment of esophageal candidiasis, however, its use is limited by significant nausea and the potential for drug interactions because of the inhibition of cytochrome P-450.

Table 2

Treatment of mucocutaneous candidiasis

	First Line Therapy	Alternative Therapy	Comments
Oropharyngeal Candidiasis	Clotrimazole troches; nystatin suspension or fluconazole	Itraconazole solution; or posaconazole or voriconazole or AmB-d oral suspension; IV echinocandin or AmB-d	Fluconazole is recommended for moderate to severe disease, and topical therapy with clotrimazole or nystatin is recommended for mild disease. Uncomplicated disease is treated for 7–14 d. For refractory disease, itraconazole, voriconazole, posaconazole, or AmB-d suspension is recommended
Esophageal Candidiasis	Fluconazole an echinocandin; or AmB-d	Itraconazole oral solution; or posaconazole or voriconazole	Oral fluconazole is preferred. For patients unable to tolerate an oral agent, IV fluconazole, an echinocandin, or AmB-d is appropriate. Treatment is for 14–21 d. For patients with refractory disease, the alternative therapy as listed or AmB-d or an echinocandin is recommended

Abbreviations: Amb-d, amphotericin B deoxycholate; IV, intravenous.

Data from Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48(5):503–35.

Patients requiring intravenous therapy should be treated with one of the echinocandins (caspofungin, micafungin, or anidulafungin), rather than amphotericin B, because of their better toxicity profiles. Echinocandins inhibit synthesis of β(1,3)- d -glucan, an essential component of the fungal cell wall. Mammalian cells do not require β(1,3)- d -glucan, thereby limiting potential toxicity. Relapse rates are higher with echinocandins when compared with azoles, and echinocandins are used as second line therapeutic agents if treatment with azoles has failed. Amphotericin B is reserved for esophageal candidiasis during pregnancy and in patients with drug-resistant candidiasis.

OPC is a local infection. Risk factors include radiation, chemotherapy, antibiotics, and corticosteroids. Treatment is with local agents such as nystatin or clotrimazole.

Prophylaxis

Patients at risk of developing OPC may be given antifungal prophylaxis with topical antifungals, such as clotrimazole or miconazole.

Viral Infections

Viral infections of the esophagus are caused by herpes simplex virus (HSV), cytomegalovirus (CMV), and uncommonly by, varicella-zoster virus (VZV). Diagnosis can be established by endoscopic biopsy. In advanced stages, all 3 viruses may cause small mucosal ulcerations. Biopsies taken from the edge of an HSV-related ulcer show intranuclear inclusions and multinucleated giant cells. Inclusions can also be detected by immunohistochemistry, using monoclonal antibodies to HSV. Biopsies of CMV lesions show intranuclear inclusions in fibroblasts and endothelial cells.

For patients with HSV esophagitis, acyclovir (400 mg orally 5 times daily for 14–21 days or 5 mg/kg intravenously every 8 hours for 7–14 days) is the therapeutic agent of choice. Acyclovir resistance in HSV results from mutations in the thymidine kinase (TK) gene of HSV. Viruses with TK mutations are generally cross-resistant to valacyclovir but remain susceptible to drugs that act directly on DNA polymerase, such as foscarnet. Cases of severe persistent infection with acyclovir-resistant HSV occur almost exclusively in immunocompromised patients. Famciclovir or valacyclovir can be considered in patients able to tolerate oral therapy, although there is limited clinical experience with these drugs in the treatment of HSV-associated esophagitis.

VZV esophagitis is initially treated with intravenous acyclovir because these patients usually have disseminated infection. After clinical improvement, treatment may be changed to an oral agent as used for HSV esophagitis.

CMV esophagitis is treated with intravenous ganciclovir (5 mg/kg twice daily) or foscarnet sodium (90 mg/kg twice daily) for 3 to 6 weeks. The role of maintenance treatment after the clearance of infection is not well defined. Valganciclovir is an oral precursor of ganciclovir. Although valganciclovir has been approved for treatment of CMV retinitis in patients with AIDS and is used for prophylaxis against CMV infection in solid-organ transplant recipients, its role in CMV GI disease has not been studied. At a dose of 900 mg daily, valganciclovir produces systemic drug exposure equivalent to 5 mg/kg of intravenous ganciclovir.

Bacterial Infections

Bacterial esophagitis can occur in immunocompromised patients and is usually polymicrobial, derived from oral flora. Diagnosis is made by endoscopic biopsies that demonstrate the presence of bacterial clusters mixed with necrotic epithelial cells. Treatment with broad-spectrum antibiotics is usually successful.

Radiation-Induced Esophagitis

Radiation-induced esophagitis can occur during external beam radiotherapy of lung, head and neck, and esophageal cancers. Acute radiation esophagitis is primarily caused by injury to the rapidly dividing cells of the basal epithelial layer, with subsequent thinning and denudation of esophageal mucosa. The severity of esophagitis depends on radiation dose and is exacerbated by concurrent use of chemotherapeutic agents such as cisplatin. Patients complain of odynophagia, dysphagia, and chest pain. Endoscopic findings include erythema, edema friable mucosa, ulcerations, or strictures.

Treatment includes use of local anesthetics such as viscous lidocaine hydrochloride and systemic narcotic analgesics and acid suppression with proton pump inhibitors and H ₂receptor antagonists. Esophageal strictures are treated by endoscopic dilation and refractory strictures may require placement of plastic stents. In patients with tracheoesophageal fistula due to esophageal cancer, self-expanding metal or plastic stents are the treatment of choice and they can achieve fistula closure in 70% to 100% of patients.

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