INTRODUCTION — The management of nausea and vomiting in cancer patients is a challenging task. Gastroparesis is one of the most underdiagnosed problems in cancer patients and is often overlooked as a potential etiology of chronic nausea and vomiting.

While the exact prevalence is not known, gastroparesis is common among patients with upper gastrointestinal tract tumors (gastric, pancreatic, esophageal, and biliary) [1,2]. Pancreatic cancer-associated gastroparesis is common. Patients with pancreatic cancer often present with nausea and vomiting in the absence of mechanical obstruction [3]. These patients may also have a more generalized disorder of gastrointestinal motility, with components of dysphagia and abnormal small bowel motility (intestinal pseudo-obstruction, "functional ileus"). (See "Chronic intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis".)

Gastroparesis is important to recognize for many reasons:

●The consequences of malignancy-associated gastroparesis can be serious, particularly in the context of other common problems that affect nutrition and fluid-electrolyte balance in cancer patients. If unrecognized and untreated, malignancy-associated gastroparesis can compound the anorexia and cachexia that often accompanies advanced cancer and the gastrointestinal side effects of specific anticancer treatments such as radiation or chemotherapy. The potential consequences include chronic nausea and vomiting, electrolyte disturbances, dehydration, hospitalization, and significant impairment of quality of life. (See "Assessment and management of nausea and vomiting in palliative care".)

●Misdiagnosis of malignancy-associated gastroparesis as chemotherapy-induced emesis can lead to delays in administration of potentially efficacious anticancer therapy.

●Gastroparesis is the single most common reason for gastric bezoar formation, and bezoars may be seen in gastroparesis of any etiology [4].

This topic review will cover malignancy-associated gastroparesis. A general discussion of the pathogenesis, etiology (including benign causes) and differential diagnosis, and treatment of delayed gastric emptying is presented elsewhere. (See "Pathogenesis of delayed gastric emptying" and "Gastroparesis: Etiology, clinical manifestations, and diagnosis" and "Treatment of gastroparesis".)

PHYSIOLOGY OF GASTRIC EMPTYING — This topic is addressed in detail elsewhere. (See "Pathogenesis of delayed gastric emptying", section on 'Anatomy and physiology of gastric motor function'.)

ETIOLOGY AND PATHOGENESIS — The etiology of malignancy-associated gastroparesis is typically multifactorial, and the contributing factors vary depending on the type of underlying cancer (table 1). Among the most important etiologic factors are paraneoplastic phenomena, direct tumor infiltration of the celiac plexus or vagus nerve, past gastrointestinal surgery, and the toxic effects of chemotherapy and radiation therapy [5]. Nerve damage from radiation has also been implicated as a cause for gastroparesis [6]. In addition, comorbidities such as poorly controlled diabetes, hypothyroidism, and neuromuscular disorders (figure 1), or the use of medications that delay gastric emptying (particularly narcotics), may also contribute to the development of gastroparesis. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)

Paraneoplastic gastrointestinal dysmotility — Paraneoplastic gastric dysmotility should be considered in otherwise unexplained gastrointestinal motor dysfunction [7]. Several patients have been described with small cell lung cancer (rarely other tumors such as breast, ovarian and pancreatic cancer, carcinoid, retroperitoneal sarcoma, Hodgkin lymphoma, and cholangiocarcinoma [8-13]) in association with a paraneoplastic gastrointestinal motility disorder [7,12,14-17]. These patients often have antineuronal nuclear (ANNA-1, anti-Hu) antibodies which can be detected by an immunofluorescence-based assay [17,18].

The autoantibody is postulated to be directed toward an epitope that is shared between the neuronal elements within the enteric nervous system and the underlying malignancy [19]. In a series of 162 patients with neurologic manifestations associated with small cell lung cancer (SCLC) and antineuronal nuclear antibodies, 12 percent had solely a gastrointestinal motility disturbance [20]. The condition presented as achalasia, gastroparesis, or chronic intestinal pseudo-obstruction.

Besides ANNA-1, other circulating autoantibodies that are associated with paraneoplastic gastrointestinal dysmotility include antineuronal antibodies type 2 (ANNA-2 or anti-Ri), amphiphysin antibody, type 1 Purkinje cell cytoplasmic antibody (PCA-1, also called anti-Yo), PCA-2, PCA-Tr, collapsing response modifier protein (CRMP) antibodies and antineuronal calcium channel antibodies of the P/Q and N-type (table 2) [21]. The two most common are ANNA-1 and N-type voltage-gated calcium channel antibodies. (See "Overview of paraneoplastic syndromes of the nervous system".)

The mechanism whereby a cross-reacting immune response results in disordered gastrointestinal motility has not been elucidated. Studies conducted in patients with SCLC and gastrointestinal dysmotility have demonstrated immune-mediated destruction of the interstitial cells of Cajal (the so-called intestinal pacemaker cells) [15]. However, others have suggested that dysmotility results from a visceral neuropathy of the myenteric plexus, caused by infiltration with lymphocytes and plasma cells, and subsequent axonal degeneration within the plexus [22].

Postsurgical dysmotility — Described extensively in the literature, postsurgical gastroparesis often follows abdominal surgery involving the stomach or the pancreas [23]. The mechanisms contributing to postsurgical gastroparesis are multiple. Vagotomy (or invasion of the vagal nerve from a tumor such as a cholangiocarcinoma), resection of the duodenum and parts of the stomach, the extent of lymphatic dissection, and the type of reconstruction can all influence the degree of postoperative gastroparesis:

●Resection of the duodenum results in reduced plasma concentrations of the hormone motilin which appears to be important for the antral contractions that clear nondigestible solid residues from the stomach during fasting. (See "Pathogenesis of delayed gastric emptying", section on 'Motor functions of the stomach regions'.)

Both standard pancreaticoduodenectomy (Whipple procedure) and pylorus-preserving pancreaticoduodenectomy are associated with gastroparesis. Gastroparesis after a pylorus-preserving pancreaticoduodenectomy occurs either in the immediate postoperative period, a condition called early gastric stasis, or later as delayed postprandial gastric emptying [24]. Loss of phase III activity of the migrating motor complex normally seen in the fasting state has been suggested as the mechanism responsible for early gastric stasis. Recovery may be prolonged.

Postprandial delayed gastric emptying occurs after the initiation of oral intake in patients who have undergone either a pylorus-preserving or standard Whipple surgery and ranges in incidence from 5 to 46 percent. Whether a pylorus-preserving procedure results in a higher frequency of delayed postprandial gastric emptying is unclear, as the available data are conflicting. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis".)

Although a periampullary malignancy is a significant risk factor for the development of delayed gastric emptying [25], delayed gastric emptying is a substantial complication after distal pancreatectomy. A review of 100 patients with distal pancreatectomy revealed an incidence of delayed gastric emptying of 24 percent.

●The stomach's accommodation response and contractility in response to distention are abolished following vagotomy and partial gastric resection. The vagus nerve carries the parasympathetic impulses to the stomach, and therefore vagotomy leads to hypo-peristalsis. While immediate early transfer of the liquid phase of the meal to the distal stomach and beyond is retained, emptying of solids is delayed. (See "Pathogenesis of delayed gastric emptying", section on 'Postvagotomy gastric motor dysfunction'.)

●Extensive upper abdominal lymph node dissection is also associated with gastroparesis, possibly as a result of damage to the extrinsic nerves, and/or intra-abdominal inflammation caused by the dissection. Recovery from postprandial gastroparesis in these cases may take six months or longer.

●Gastroparesis after surgery for gastric cancer is also influenced by the type of reconstruction. In one case series, the incidence of gastroparesis was significantly lower after a Billroth I gastrectomy than after Roux-en-Y reconstruction (4.3 versus 15.5 percent) [26].

In the Roux stasis syndrome, which can occur after a Roux-en-Y anastomosis, stasis results from incoordination of contractions in the efferent Roux limb. This causes stasis in either the gastric remnant or in the Roux limb itself. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Medications'.)

Celiac plexus injury — Physical damage to the celiac plexus, resulting from either cancer infiltration or a celiac plexus nerve block, can also lead to gastroparesis, although this appears to be a rare complication [27]. Injury to the celiac plexus affects parasympathetic input to the stomach, resulting in loss of myenteric coordination. (See "Cancer pain management: Interventional therapies", section on 'Nonneurolytic blocks' and "Endoscopic ultrasound-guided celiac plexus interventions for pain related to pancreatic disease", section on 'Complications'.)

High-dose chemotherapy and stem cell transplantation — Problems with gastric motor function are reported in up to one-half of patients undergoing hematopoietic stem cell transplantation (HSCT), both autologous and allogeneic [28,29]. Viral infection (cytomegalovirus, herpes simplex virus) has been implicated in some reports [28]. However, gastric dysmotility with abnormalities in gastric myoelectric activity has been documented in the absence of viral infection among patients undergoing high-dose chemotherapy with autologous HSCT [29,30].

In addition, an upper gastrointestinal form of acute graft versus host disease (GVHD) has been described that is characterized by anorexia, dyspepsia, food intolerance, nausea, and vomiting. This is more common following allogeneic than autologous HSCT, largely because of the higher rate of graft versus host disease in this setting [29]. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Upper gastrointestinal tract'.)

Radiation therapy — Gastroparesis is rarely reported as a complication of abdominal radiation therapy [31]. Both gastric and duodenal obstruction are reported after radiation therapy for cholangiocarcinoma and are presumably due to radiation fibrosis [32,33]. There is little information on the overall incidence of radiation induced gastric dysmotility.

CLINICAL FEATURES AND DIAGNOSIS — The presenting symptoms of cancer-associated gastroparesis include nausea, abdominal pain, early satiety, emesis, bloating, and weight loss. In one study, nausea was the major complaint in 93 percent of patients with gastroparesis, 89 percent had abdominal pain, 86 percent experienced early satiety, and vomiting occurred in 68 percent [34].

However, nonspecific symptoms such as these are not uncommon among patients who have cancer, and may be attributed to the malignancy itself or various treatment modalities, including surgery, chemotherapy, or radiation therapy. Thus, in order to avoid misdiagnosis, clinicians must maintain a high index of suspicion for the diagnosis of gastroparesis.

Malignant gastroparesis should always be included in the differential diagnosis of patients who present the aforementioned constellation of symptoms, especially if the symptoms become more pronounced after ingestion of solid meals and if there is vomiting of food eaten several hours earlier. Malignancy-associated gastroparesis should particularly be suspected in cancer patients experiencing refractory, otherwise-unexplained nausea and vomiting.

Physical examination may be unrevealing or there may be epigastric distention or tenderness, but not guarding or rigidity. A succussion splash may be heard on auscultation of the epigastric area; this physical finding is due to stasis of the gastric contents. (See "Approach to the adult with nausea and vomiting".)

Diagnostic workup — The initial steps of the diagnostic workup are to exclude mechanical obstruction and side effects from narcotics, and to assess nutritional status. Upper gastrointestinal endoscopy should be obtained in most cases. The endoscopic appearance of retained food and a dilated distended stomach with decreased peristalsis is strongly indicative of gastroparesis. If there are signs and/or symptoms to suggest small bowel pathology (such as a partial small bowel obstruction or generalized gastrointestinal dysmotility), an oral contrast upper GI tract series with small bowel follow-through is indicated.

Routine laboratory testing is not useful for the diagnosis of gastric stasis itself, although it may help to identify diseases that are associated with delayed gastric emptying, to rule out other disorders, and assess nutritional status. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Laboratory studies'.)

Gastric emptying scintigraphy — The standard test for establishing the diagnosis of gastroparesis is gastric scintigraphy following a standardized solid meal. Consensus standards for performing and reporting gastric emptying scintigraphy are available [35]. The suggested protocol involves a low fat meal (bread, jam, and scrambled egg substitute with technetium-99m pertechnetate) with imaging at zero, one, two, and four hours after meal ingestion. Normal values for the percent remaining in the stomach at the key time points are 37 to 90 percent at one hour, 30 to 60 percent at two hours, and 0 to 10 percent at four hours. In clinical practice, the most useful parameters to define gastroparesis are gastric retention of >10 percent at four hours, and >70 percent at two hours [35,36]. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Scintigraphic gastric emptying'.)

Gastric emptying scintigraphy can be utilized both for diagnosis and to monitor the effectiveness of prokinetic therapy, although the repeated exposure to radiation may limit the utility of frequent testing [37]. (See 'Alternatives to scintigraphy' below.)

Liquid-phase gastric emptying (with the radioactive technetium-99m pertechnetate mixed in orange juice) can be performed if the patient cannot tolerate solids or when mechanical obstruction cannot be excluded. Delayed gastric emptying is defined as greater than 50 percent retention of gastric contents at 30 minutes.

The gastric emptying study was developed for use in patients with normal gastric anatomy. It may be difficult to interpret the study in postsurgical patients as there are no standardized controls for patients, with a subtotal or total gastrectomy. The study also does not quantify intestinal dysmotility, which also occurs in this patient population. Finally, scintigraphy bears some radiation hazard and may therefore not be suitable for repeated investigations.

Alternatives to scintigraphy — Alternative approaches for assessment of gastric emptying include wireless motility capsule testing and ¹³C breath testing using octanoate or spirulina incorporated into a solid meal. These tests have the advantage of avoiding the radiation associated with scintigraphy. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Alternatives to scintigraphy'.)

Other tests for gastric motility, such as cutaneous electrogastrogram (EGG) and MRI, are considered investigational and are discussed elsewhere. (See "Gastroparesis: Etiology, clinical manifestations, and diagnosis", section on 'Other tests'.)

Quantifying symptom severity — Several tools are available to quantify the severity of symptoms of gastroparesis.

The patient assessment of upper gastrointestinal disorders-symptom severity index (PAGI-SYM SF-36) is a self-reported instrument that assesses the severity of symptoms related to gastroparesis, gastroesophageal reflux, and dyspepsia. It has been validated and can be used to measure the efficacy of therapy [38].

The Gastroparesis Cardinal Symptom Index (GCSI) was developed to assess the severity of symptoms associated with gastroparesis. It evaluates nine symptoms using a scale from 0 to 5 with a maximal score of 5 [39]. This validated symptom score measures three subscales: post prandial fullness/early satiety, nausea/vomiting, and bloating. Good correlation has been seen between the short-form-36 item health survey (SF-36) and GCSI [39].

Quality of life instruments for gastric or pancreatic cancer such as the Functional Assessment of Cancer Therapy (FACT-G) or the European Organization for Research and Treatment of Cancer (EORTC) PAN26 do not include a formal assessment for cancer-associated gastroparesis, although the symptoms of this disorder are recorded.

The severity of treatment or procedure-related gastroparesis may be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) scale (table 3).

MANAGEMENT — Longstanding untreated malignancy-associated gastroparesis has serious nutritional and metabolic consequences. All patients should be assessed at baseline for dehydration, electrolyte abnormalities, malnutrition, and weight loss. Comorbidities such as poorly controlled diabetes and hypothyroidism need to be corrected, and medications that contribute to delayed gastric emptying should be discontinued [36].

General approach — Patients with mild nutritional impairment can be managed with dietary and behavioral modification, as well as oral prokinetic and antiemetic medications. When a patient has evidence of malnourishment (hypoalbuminemia and ≥10 percent weight loss), enteral nutrition should be considered in addition to prokinetic and/or antiemetic medications. (See 'Nutrition issues' below.)

For patients with severe fluid and electrolyte disturbances or hypotension, hospitalization may be needed. Initial management includes correction of the fluid and electrolyte disturbances, intravenous administration of prokinetic and antiemetic agents, nasogastric or gastrostomy tube placement to decompress the stomach, and consideration for surgical, radiological, or endoscopic jejunostomy tube placement for longer-term decompression and feeding, if needed.

Dietary and behavioral modification — Guidelines for dietary and behavioral modification are focused on measures that contribute to enhanced gastric emptying. For the most part, these recommendations have been derived empirically rather than from controlled studies (see "Treatment of gastroparesis", section on 'Dietary modification'):

●Patients should be encouraged to eat while upright and stand or walk afterwards as gravity and body movement help in gastric emptying.

●Increasing the liquid nutrient component of the ingested meal is helpful, as liquids transit more rapidly than solids [40,41].

●Small, frequent, low-fat, low-residue meals are appropriate for patients with gastroparesis in order to avoid gastric distension and symptoms of bloating, early satiety, and nausea. Lipids and indigestible fiber delay gastric emptying.

●Alcohol and tobacco smoking should be avoided because both decrease antral contractility and slow gastric emptying.

●Patients should avoid dehydration by ensuring an adequate daily fluid intake.

●Nutritional and vitamin supplementation are often required.

Pharmacotherapy — The pharmacologic agents used for cancer-associated gastroparesis closely parallel those used for non-cancer associated gastroparesis (table 4). There are no randomized trials that specifically address the efficacy of any agent for the treatment of malignancy-associated gastroparesis. Prokinetic and antiemetic agents are the mainstay of therapy; specific goals are to accelerate gastric emptying, improve symptoms, and prevent nausea or emesis. For most patients, we start with metoclopramide.

The benefit of oral prokinetics for improving gastric emptying was addressed in a systematic review included 36 clinical studies involving 514 patients who were treated with prokinetics for gastroparesis [42]. They concluded that erythromycin had the strongest effect on gastric emptying as compared with domperidone, cisapride or metoclopramide. However, these investigators and others have shown that objective improvement in gastric emptying does not necessarily correlate with symptomatic improvement. Very little information is available regarding symptom relief with prokinetic agents. In a systematic review of the benefits of oral erythromycin for gastroparesis, only five of 35 published studies included any form of symptom assessment as a study endpoint [43]. Symptom improvement was reported in 26 of 60 patients (43 percent).

The only three prokinetic agents that remain available in the United States are metoclopramide, erythromycin, and tegaserod. Of these agents, the only one approved specifically for treatment of gastroparesis is metoclopramide. Cisapride and domperidone are not readily available in the United States and require an Investigational New Drug Application (IND).

What follows is a general discussion of the data that are available regarding benefit of prokinetics and antiemetics in malignancy-associated gastroparesis. The data in patients with non-malignant causes of delayed gastric emptying are summarized elsewhere. (See "Treatment of gastroparesis".)

Metoclopramide — Metoclopramide (Reglan) is a combined type 4 serotonin receptor (5-HT4) agonist and dopamine D(2) receptor antagonist. It promotes gastric emptying and intestinal transit by facilitating gastrointestinal cholinergic and nitrergic (nitric oxide mediated) activity. It also has antiemetic properties that are related to central and peripheral inhibition of dopamine receptors. (See "Characteristics of antiemetic drugs", section on 'Benzamides'.)

Retrospective reports support the benefit of metoclopramide (5 to 10 mg taken orally before meals and at bedtime, or 5 mg subcutaneously two to four times daily) for cancer patients with gastroparesis and chronic nausea from a variety of causes [44,45]. Benefits include improvement in symptoms of nausea, vomiting, abdominal pain, postprandial fullness, weight loss, and early satiety.

An intranasal preparation of metoclopramide is approved for use in diabetic gastroparesis (one spray [15 mg] in one nostril four times daily [30 minutes prior to each meal and at bedtime] for two to eight weeks depending on symptomatic response). Although specific data are not available, off-label use could be considered for malignancy-associated gastroparesis. (See "Treatment of gastroparesis", section on 'Metoclopramide'.)

A concern is that metoclopramide readily crosses the blood-brain barrier, where D(2) receptor antagonism can cause akathisia, tardive dyskinesia, and other extrapyramidal symptoms. In 2009, the US Food and Drug Administration (FDA) issued a black box warning regarding long-term or high-dose use of metoclopramide because of the risk of developing tardive dyskinesia, which is not reversible. While the risk of tardive dyskinesia with long-term administration has been estimated to be between 1 and 10 percent, a 2010 literature review noted that evidence from large, national prescription databases in the United Kingdom and Sweden recorded a far lower incidence of tardive dyskinesia (less than one percent) than was suggested from case series that were typically collected at tertiary referral clinics [46]. The risk of adverse effects from metoclopramide can be reduced if the dose is kept at or below 40 mg per day. However, clinicians should document the discussion of potential adverse effects of metoclopramide in the medical record when they prescribe metoclopramide for long-term use.

Erythromycin — Erythromycin is a bacteriostatic macrolide antibiotic with prokinetic properties that is widely used for diabetic gastroparesis. It is a potent motilin agonist that improves gastric emptying by inducing gastric peristalsis. (See "Pathogenesis of delayed gastric emptying", section on 'Anatomy and physiology of gastric motor function'.)

Intravenous administration of erythromycin (erythromycin lactobionate, 3 mg/kg every eight hours) may be used to "restart" or "kick-start" the stomach during acute episodes of gastric stasis in which oral intake is not tolerated. Infusion should be performed over 45 minutes to avoid pain on injection and damage to peripheral veins. (See "Treatment of gastroparesis", section on 'Macrolide antibiotics'.)

In patients with diabetic gastroparesis, erythromycin is generally less effective when taken orally as compared with intravenously. Tachyphylaxis may limit long-term efficacy, although this is not universal [47-49]. Lack of efficacy after one month should alert the clinician to this possibility.

Evidence of the effectiveness of oral erythromycin in patients with malignancy-associated gastroparesis is limited. In retrospective reports, improvement in symptoms has been seen in patients who developed gastroparesis after radiation therapy and bone marrow transplantation [29,42,50,51].

As with metoclopramide, potential side effects of erythromycin are a concern, especially with long-term use. These include gastrointestinal toxicity, ototoxicity, pseudomembranous colitis, the induction of resistant bacterial strains, and the risk of sudden death due to long QT syndrome, which is further increased when the drug is used in conjunction with other medications that inhibit cytochrome P450 3A4 (CYP3A4) (table 5). (See "Acquired long QT syndrome: Definitions, causes, and pathophysiology", section on 'Medications'.)

Tegaserod — Tegaserod (Zelnorm) is a partial 5-HT4 receptor agonist that stimulates intestinal secretions, increasing peristalsis. It was approved in the United States for constipation-predominant irritable bowel syndrome and chronic idiopathic constipation but was removed from the market in 2007 because of serious cardiovascular adverse events (eg, angina, heart attacks, and strokes).

There are only a few published reports on the benefits of tegaserod (which is generally given at a dose of 6 mg twice daily prior to meals) in patients with gastroparesis [52,53]. Tegaserod was withdrawn from the United States market in 2007, but it was reintroduced in 2019 with an indication for treatment of women with irritable bowel syndrome and predominant constipation. Off-label use could be considered for patients with malignancy-associated gastroparesis who do not respond or have adverse events with metoclopramide.

Cisapride — Cisapride (Propulsid) is a gastrointestinal prokinetic agent that stimulates serotonin receptors and releases acetylcholine from the myenteric plexus, inducing intestinal peristalsis.

Cisapride accelerates gastric emptying of solids and liquids in a variety of gastric stasis syndromes; this effect has been maintained during long-term (one year) open trials. Although it is available in several other countries, cisapride is only available in the United States through a special IND program since it has been associated with cardiac dysrhythmias when administered with medications that are inhibitors of the CYP3A4 metabolizing isoenzyme (table 5). (See "Treatment of gastroparesis", section on 'Cisapride'.)

Domperidone — Domperidone (Motilium) is a dopamine antagonist that stimulates gastrointestinal motility by blocking dopamine D1 receptors and by inhibiting release of acetylcholine through a blockade of D2 receptors. (See "Treatment of gastroparesis", section on 'Domperidone'.)

Domperidone is not approved for use by the FDA but is available in Canada and other countries. However, the FDA has encouraged "physicians who would like to prescribe domperidone for their patients with severe gastrointestinal disorders that are refractory to standard therapy to open an IND Application."

Antiemetic agents — Phenothiazines such as prochlorperazine and promethazine are commonly used to control nausea in patients with gastroparesis. Prochlorperazine acts centrally by inhibiting the dopamine receptors in the chemoreceptor trigger zone in the medulla and peripherally by blocking the nerve. It can be administered orally, parenterally, or rectally.

The type 3 serotonin receptor (5-HT3) antagonists such as ondansetron, granisetron, or tropisetron are used for treatment and prevention of chemotherapy induced nausea and vomiting. Drugs of this class selectively bind to 5-HT3 receptors on the vagus nerve, blocking signals to the vomiting center; they also act centrally in the chemoreceptor trigger zone in the area postrema. (See "Characteristics of antiemetic drugs" and "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".)

The role of 5-HT3 antagonists in the management of malignant gastroparesis is controversial. Drugs of this class confer no advantage over other antiemetics in patients with gastric stasis syndromes. However, a trial of ondansetron or a related agent is reasonable for patients who fail to respond to a prokinetic agent, or a phenothiazine antiemetic.

Other options for refractory symptoms include mirtazapine [54,55], a tricyclic antidepressant, or dronabinol.

Aprepitant — Aprepitant is a neurokinin-1 receptor antagonist available in oral and parenteral forms. It has been shown to alleviate the emetic effects of the neurotransmitter substance P. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Neurokinin-1 receptor antagonists'.)

Refractory diabetes-associated and idiopathic gastroparesis have been successfully managed with long-term aprepitant [56-58]. In addition, case reports suggest that aprepitant can improve nausea and vomiting in pediatric patients who have gastroparesis after stem cell transplantation [59]. However, a four-week randomized placebo-controlled trial of aprepitant in patients with gastroparesis of a variety of etiologies did not show a decrease in nausea with aprepitant, although there were varying effects on secondary outcomes of gastroparesis symptom severity [60]. Specific trials are needed to address the benefit of aprepitant in malignant gastroparesis.

Treatment considerations for paraneoplastic dysmotility — For patients with paraneoplastic gastrointestinal dysmotility, antitumor therapy may improve symptoms. Although symptoms often do not improve in cases such as this with paraneoplastic autonomic dysfunction, occasional patients have substantive and sustained clinical improvement with antitumor or nonspecific immune therapy. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Autonomic neuropathy'.)

Management options for refractory cases — For the 2 to 5 percent of patients with severe gastroparesis who have minimal or no improvement of symptoms with dietary and behavioral modification and pharmacotherapy, more invasive methods for symptom control include placement of a venting gastrostomy and/or jejunostomy tube, or surgery. In addition, referral to gastroenterology specialty clinic is recommended. Other options that may be tried at experienced centers are placement of a gastric electrical stimulator or peroral pyloromyotomy.

Decompression — Percutaneously or laparoscopically placed gastrostomy or jejunostomy tubes can decompress a dilated upper gut. In patients with more generalized motility disorders, this is an effective method to eliminate frequent emesis and reduce the need of hospitalization for acute exacerbations of dysmotility. However, decompression is only rarely necessary. In patients without permanent enterostomy tubes, intravenous erythromycin usually relieves acute gastric stasis rapidly. (See "Treatment of gastroparesis", section on 'Decompression and feeding'.)

Although helpful for decompression, a gastrostomy tube alone is of questionable value for nutritional support without a jejunal tube placement. A radiologically or endoscopically placed double-lumen enteric tube with separate gastric and jejunal ports is not ideal because of the risk of migration of the jejunal tube into the stomach. The advantages and disadvantages of several nonpharmacologic interventions for refractory gastroparesis are outlined (table 6).

Feeding jejunostomy tubes are discussed below. (See 'Enteral nutrition' below.)

Other operative interventions — Completion gastrectomy with preservation of only a small cuff of gastric tissue provides long-term symptom relief in 43 to 67 percent of patients with postsurgical gastroparesis [61]. However, this is a major surgical procedure, and cancer patients with a limited life span may not be appropriate candidates. (See "Treatment of gastroparesis", section on 'Surgery'.)

Roux-en-Y stasis syndrome can be particularly difficult to manage medically and may benefit from surgical intervention. Patients with Roux-en-Y stasis are treated the same way as chronic intestinal pseudo-obstruction, with emphasis on hydration, antiemetics and prokinetic agents. However, some patients who have retained food predominantly in the gastric remnant improve after subtotal gastrectomy, retaining only a cuff of proximal stomach anastomosed to the Roux limb. (See "Chronic intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis".)

Surgical placement of a feeding jejunostomy is discussed below.

Gastric electrical stimulation — Gastric electrical stimulation (GES) improves symptoms of idiopathic gastroparesis in patients who do not respond to standard medical therapy with diet, prokinetics, and antiemetics. In the United States in March 2000, the gastric stimulator was given a humanitarian device exemption by the FDA for the treatment of diabetic and idiopathic gastroparesis, which has been refractory to medical management. (See "Electrical stimulation for gastroparesis".)

Temporary gastric electrical stimulation (tGES) has been used in malignancy-associated gastroparesis, with symptomatic benefit [62]; however, prospective studies of GES in this population are needed.

Endoscopic therapies — Endoscopic options for management of refractory gastroparesis include placement of a transpyloric stent and endoscopic pyloromyotomy (gastric peroral endoscopic myotomy [G-POEM]). However, nearly all of the data are in patients with benign causes of gastroparesis, including postsurgical, and there are no data from randomized sham-controlled trials, which are required to establish the role of these therapeutic approaches in patients with gastroparesis. (See "Treatment of gastroparesis", section on 'Other therapies with limited or unclear role' and "Peroral endoscopic myotomy (POEM)".)

Botulinum treatment — Botulinum toxin reduces the tone and phasic contractions of the pylorus by preventing cholinergic contractile activity. Although small case series reported improved symptoms and gastric emptying after botulinum toxin injection into the pylorus, at least two randomized controlled trials have failed to demonstrate any benefit. Until further trials are available, routine use of botulinum toxin in malignancy-associated gastroparesis cannot be recommended. (See "Treatment of gastroparesis", section on 'Other therapies with limited or unclear role'.)

Nutrition issues — For gastroparetic patients who are unable to eat because of severe nausea and vomiting, every attempt should be made to provide enteral nutrition, which is less expensive, associated with fewer complications, and may enhance gastrointestinal motility. Parenteral nutrition should only be considered if attempts at small bowel feeding have not been successful.

Enteral nutrition — Enteral nutrition is preferably delivered via an endoscopic or surgically placed jejunostomy tube (table 6). Gastrostomy tubes should be avoided, if possible, as they may lead to partial pyloric obstruction, impair recovery of gastric emptying and they can interfere with placement of electrodes for neurostimulation, if indicated [5]. (See 'Gastric electrical stimulation' above.)

Before placing a permanent jejunal tube, it is appropriate to perform a 48- to 72-hour trial of nasojejunal feeding to confirm that the patient will be able to handle infusion of nutrient at a rate that delivers an adequate caloric and protein level [63]. For patients requiring long-term enteral nutrition, surgically placed jejunostomy tubes are preferable. Endoscopically placed jejunal tubes often migrate back into stomach, particularly in patients with recurrent vomiting.

Enteral feeding is effective in the long-term care of patients with gastroparesis, although there are few data in patients with malignancy-associated gastroparesis. In a study of 26 patients with diabetic gastroparesis, surgically placed jejunostomy improved quality of life and decreased the frequency of hospitalizations [64]. Furthermore, one-half of the patients were able to resume full oral intake and have the jejunostomy tube removed. Complications of jejunal tube placement include infection, tube dysfunction, and tube dislodgement.

The choice of enteral formula in patients with gastroparesis is based on practical experience rather than controlled studies. The main principle is to use an iso-osmolar, non-elemental liquid supplement.

Indications for parenteral nutrition — Parenteral nutrition is seldom necessary in patients with gastric stasis unless it is part of a generalized motility disorder. For patients with malignancy-associated gastroparesis, parenteral nutrition is indicated if they have failed previous attempts of enteral nutrition due to intolerance or complications related to enteral feeding. The morbidity of parenteral nutrition is considerable and includes vein thrombosis, sepsis, and hepatic cholestasis.

PROGNOSTIC IMPACT OF GASTROPARESIS — There are few data on the impact of malignant gastroparesis on prognosis. In a single institution review of 95 patients diagnosed with gastroparesis, 59 postsurgical and 36 with cancer and nonsurgical gastroparesis, median survival was significantly better for surgical versus nonsurgical patients (21 versus 6.5 months) [65].

SUMMARY AND RECOMMENDATIONS

●Gastroparesis is one of the most underdiagnosed problems in cancer patients and is often overlooked as a potential etiology of nausea and vomiting. (See 'Introduction' above.)

●The etiology is often multifactorial, and the contributing factors vary depending on the type of underlying cancer. Among the most important are paraneoplastic phenomena, direct tumor infiltration, past gastrointestinal surgery, and the toxic effects of chemotherapy and radiation therapy. Poorly controlled diabetes, hypothyroidism, other neuromuscular disorders, and use of medications that affect gastric emptying (particularly opioids) may also contribute. (See 'Etiology and pathogenesis' above.)

●Presenting symptoms include nausea, abdominal pain, early satiety, vomiting, bloating, and weight loss. (See 'Clinical features and diagnosis' above.)

●The initial steps of the diagnostic workup are to exclude mechanical bowel obstruction and side effects from narcotics as a cause of symptoms. Patients should be assessed for dehydration, electrolyte abnormalities, malnutrition, and weight loss. Upper gastrointestinal endoscopy should be obtained in most cases. The standard test for establishing the diagnosis of gastroparesis is gastric scintigraphy following a standardized solid meal. (See 'Diagnostic workup' above.)

Management

●Patients with mild nutritional impairment can be managed with dietary and behavioral modification, and oral prokinetic and antiemetic medications. When a patient has evidence of malnourishment (hypoalbuminemia and ≥10 percent weight loss), enteral nutrition should be considered in addition to prokinetic and/or antiemetic medications. For patients with severe fluid and electrolyte disturbances or hypotension, hospitalization may be needed. (See 'General approach' above.)

●Dietary modifications include small, frequent, low-fat, low-residue meals; eating while upright and walking or standing after meals; avoidance of alcohol, tobacco, and carbonated drinks; and increased intake of liquid as compared with solid nutrition. (See 'Dietary and behavioral modification' above.)

●The only three prokinetic agents that are commercially available in the United States are metoclopramide, erythromycin, and tegaserod; none of these agents is ideal. In countries in which it remains available, we suggest cisapride rather than metoclopramide or erythromycin for subacute or chronic delayed gastric emptying (Grade 2C). Several precautions must be taken (avoidance of concurrent drugs that are inhibitors of cytochrome P450 3A4 [CYP3A4] (table 5)), and the maximum dose should be kept below 1 mg/kg or 60 mg per day in adults. (See 'Pharmacotherapy' above.)

In settings where cisapride is not available, we suggest domperidone (40 to 80 mg orally per day in four divided doses) in countries where it is approved, metoclopramide (either subcutaneous or orally, 5 to 10 mg three to four times daily, or intranasally [15 mg four times daily]), or erythromycin (125 to 250 mg orally three times daily) (Grade 2C).

Potential side effects of erythromycin remain a concern (table 4), especially the risk of sudden death due to long QT syndrome when used in patients taking medications that inhibit CYP3A4 (table 5). (See 'Erythromycin' above.)

The risk of adverse effects from metoclopramide can be reduced if the dose is kept at or below 40 mg per day, but the risk of potentially permanent extrapyramidal side effects with long-term use beyond three months must be discussed with patients. (See 'Metoclopramide' above.)

Off-label use of tegaserod could be considered for patients with malignancy-associated gastroparesis who do not respond or have adverse events with metoclopramide. (See 'Tegaserod' above.)

All these prokinetics should be administered 10 to 15 minutes before meals; an additional dose before bedtime might be useful.

During acute episodes of gastric stasis in which oral intake is not tolerated, we suggest intravenous administration of erythromycin (erythromycin lactobionate, 3 mg/kg every eight hours) to "restart" or "kick-start" the stomach (Grade 2B). An alternative is to use intranasal (15 mg four times daily) or subcutaneous metoclopramide (5 to 10 mg three times daily) after a test dose to exclude extrapyramidal adverse effects (Grade 2C).

●Antiemetics may help with nausea and vomiting. We recommend a drug of the phenothiazine class rather than a serotonin receptor antagonist (Grade 1B). (See 'Antiemetic agents' above.)

A trial of ondansetron or a related agent is reasonable for patients who fail to respond to a prokinetic agent or a phenothiazine antiemetic.

●Patients who have persistent symptoms despite maximal dietary modification and pharmacologic therapy should be considered for more invasive means of palliation. Nonpharmacologic interventions such as drainage gastrostomy and feeding jejunostomy tubes provide symptom palliation and nutritional support. In addition, another option that may be tried at experienced centers is placement of a gastric electrical stimulator. (See 'Management options for refractory cases' above.)

In the United States, another option is to pursue an emergency investigational new drug (IND) for cisapride or domperidone from the US Food and Drug Administration (FDA). (See 'Cisapride' above and 'Domperidone' above.)