Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, Minnesota
Gastrointestinal (GI) dysmotility that occurs in the setting of malignancy may not result from direct tumor invasion, infections, metabolic derangements, or chemotherapy. Such disorders of motility are characterized as paraneoplastic GI dysmotility. This condition is most commonly associated with small cell lung cancer (SCLC), with symptoms usually preceding the diagnosis of cancer.1 Paraneoplastic GI dysmotility has a wide spectrum of clinical presentations, including achalasia, gastroparesis, chronic intestinal pseudo-obstruction, and constipation. Diagnosis often requires a high degree of clinical suspicion as well as serologic testing with widely available onconeuronal antibodies such as type 1 anti–neuronal nuclear antibody (ANNA-1), also known as anti-Hu antibody (which is directed against the Hu family of RNA nuclear binding proteins). This test has become the first line of testing when paraneoplastic dysmotility is suspected.
The pathophysiology of paraneoplastic GI dysmotility is not completely understood. Lymphoplasmacytic destruction of myenteric plexus neurons has been proposed based on histologic studies that show a decreased number of ganglion cells, replacement of neurons by Schwann cells and collagen, or a decrease in interstitial cells of Cajal; however, smooth muscle cells are typically spared.2,3 The destruction of myenteric neurons is thought to result from autoimmune mechanisms. This is consistent with recent reports of non-neoplastic autoimmune GI dysmotility. Thus, in addition to ANNA-1, voltage-gated calcium channel antibodies, neuronal nicotinic acetylcholine receptor antibodies, and Purkinje cell cytoplasmic antibodies have been seen in patients with paraneoplastic GI dysmotility.1
Although SCLC is the cancer most commonly associated with paraneoplastic GI dysmotility, cancers arising in the ovaries, breasts, stomach, esophagus, and bronchial carcinoids have also been associated with paraneoplastic GI dysmotility. A subset of ANNA-1–positive SCLC patients in 1 study were found to have synchronous malignancies.4 Subacute (<6 months) onset of rapidly progressive, disabling symptoms in high-risk patients (eg, age
>50 years, history of smoking) should prompt suspicion for a paraneoplastic phenomenon.5 Gastroparesis and chronic intestinal pseudo-obstruction are the 2 most common paraneoplastic GI dysmotility syndromes. Unfortunately, the diagnosis of paraneoplastic GI dysmotility is difficult because dysmotility symptoms have poor specificity for paraneoplastic processes and poor negative predictive values in the absence of antibodies. To exclude the possibility of a false-positive serology test, a more aggressive search with mediastinal computed tomography imaging and bronchoscopy is generally recommended to detect an occult neoplasm (eg, SCLC) in the presence of both suggestive dysmotility symptoms and ANNA-1.1
The treatment of paraneoplastic GI dysmotility centers on management of the underlying malignancy. However, dysmotility can persist even after the cancer is in complete remission.6 The usual management of dysmotility (with antiemetics, prokinetics, or laxatives) is often suboptimal, leading to severe malnutrition and wasting, even though the cancer itself may be under control. There is an unmet clinical need for management of paraneoplastic GI dysmotility. Targeting the autoimmune pathogenesis with high-dose corticosteroids, cyclophosphamide, intravenous immunoglobulin (IVIG), rituximab (Rituxan, Genentech), or plasmapheresis has been associated with limited success to date.7
The case reported by Zhang and colleagues described a patient who had metastatic non-SCLC confirmed by a positron emission tomography scan and a biopsy of a cervical node and who had presumed paraneoplastic GI dysmotility (gastroparesis and diffuse colonic dilation).8 The patient failed initial treatment with a 4-day course of IVIG—although the usual dose for the treatment of autoimmune dysmotility is six 5-day cycles—but he was successfully treated with methylnaltrexone (Relistor, Salix).8 The case report also highlighted nonobstructive biliary dilation as a rare manifestation of paraneoplastic GI dysmotility.
It is unclear from the case report by Zhang and colleagues whether there was metastatic spread beyond the cervical node, and it is assumed that the potential adverse effects of opioid use were excluded when the patient was enrolled in a comprehensive strategy to manage the presumed paraneoplastic GI dysmotility.8 After failure of IVIG therapy, a significant improvement in bowel function was noted with a single dose of methylnaltrexone. Additional clinical clues supported the potential role of increased endogenous opioid function in this patient. Thus, the presence of colonic dilation and bile duct dilation was suggestive of high opioid effects. As the sphincter of Oddi has a high density of µ-opioid receptors, the nonobstructed dilation of the bile duct suggests a dysfunction or spasm of the sphincter.9,10 Opioid agonism is associated with gastroparesis and colonic motor dysfunction, including dilation.11
Methylnaltrexone is a subcutaneously administered, peripherally acting, µ-opioid receptor antagonist that is approved by the US Food and Drug Administration for treatment of opioid-induced constipation in patients with advanced illness who are receiving palliative care and have not received sufficient relief from laxative therapy. N-methylation of the systemic opioid antagonist naltrexone limits its ability to cross the blood–brain barrier, thus preserving central analgesic effects of co-administered opioids and reversing the effects of those opioids in the periphery, specifically in the GI tract. Methylnaltrexone has reversed morphine-induced delay in gastric emptying and oral–cecal transit time without affecting analgesia in healthy volunteers and has also been shown to reverse methadone-associated constipation and GI dysmotility.12-14 In a phase III clinical trial, 133 patients with terminal disease (58% cancer) who were taking opioids for analgesia for at least 2 weeks and who were having fewer than 3 bowel movements despite taking laxatives during the previous week were randomized to either methylnaltrexone at a dose of 0.15 mg/kg body weight or placebo every other day for 2 weeks.15 In the methylnaltrexone group, significantly more patients achieved laxation within 4 hours of the first study dose compared to patients in the placebo group (48% vs 15%). Abdominal pain and flatulence were the most commonly reported adverse effects.
Zhang and associates proposed 2 potential mechanisms to explain their patient’s improved gut motility, including a reduction in the effects of endogenous opioids in the autoimmune destruction of enteric neurons and competitive inhibition of anti-Hu antibody binding to opioid receptors.8 Additional studies are required to investigate these potential mechanisms. Opioids may also have other roles in the enhancement of cancer progression, which may have been inhibited by methylnaltrexone. Thus, reduced exposure to opioids via regional anesthesia has been associated with a decreased risk of cancer recurrence, and overexpression of µ-opioid receptors in a human non-SCLC cell line has been shown to increase
in vitro and in vivo measures of tumor growth and metastasis.16,17 Other potential effects of methylnaltrexone include inhibition of opioid-induced endothelial cell proliferation and migration via inhibition of the vascular endothelial growth factor receptor.18
Overall, the case reported by Zhang and coworkers raised interesting concepts on the mechanism of paraneoplastic GI dysmotility and documented the potential utility of methylnaltrexone for treatment of this condition; however, these observations must be replicated and systematically studied before this drug can be recommended as a treatment option.8
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