Nausea and Vomiting in Advanced Cancer: the Cleveland Clinic Protocol

How We Do It

Nausea and vomiting in advanced cancer: the Cleveland Clinic protocol

Mona Gupta, MD, Mellar Davis, MP, MD, Susan LeGrand, MD, Declan Walsh, MSc, and Ruth Lagman, MD, MPH The Harry R. Horvitz Center for Palliative Medicine, Section of Palliative Medicine and Supportive Oncology, Department of Solid Tumor Oncology, Cleveland Clinic Tausig Cancer Institute, Ohio

Nausea and vomiting are common and distressing symptoms in advanced cancer. Both are multifactorial and cause significant morbidity, nutritional failure, and reduced quality of life. Assessment includes a detailed history, physical examination and investigations for reversible causes. Assessment and management will be influenced by performance status, prognosis, and goals of care. Several drug classes are effective with some having the added benefit of multiple routes of administration. It is our institution’s practice to recommend metoclopramide as the first drug with haloperidol as an alternative antiemetic. Dexamethasone should be used for patients with central nervous system metastases or bowel obstruction. If your patient is near death, empiric metoclopramide, haloperidol or chlorpromazine is used without further investigation. For patients with a better prognosis, we exclude reversible causes and use the same first-line antiemetics, metoclopramide and haloperidol. For those who do not respond to first-line single antiemetics, olanzapine is second line and ondansetron is third. Rarely do we use combination therapy or cannabinoids. Olanzapine as a single agent has a distinct advantage over antiemetic combinations. It improves compliance, reduces drug interactions and has several routes of administration. Antiemetics, anticholinergics, octreotide and dexamethasone are used in combination to treat bowel obstruction. In opiod-naïve patients, we prefer haloperidol, glycopyrrolate and an opioid as the first-line treatment and add or substitute octreotide and dexamethasone in those who do not respond. Non-pharmacologic interventions (mechanical stents and percutaneous endoscopic gastrostomy tubes) are used when nausea is refractory to medical management or for home-going management to relieve symptoms, reduce drug costs and rehospitalization.

ausea and vomiting are common in ad- vous system, metabolic, medication, and psychi- vanced cancer and frequently unrelated atric etiologies (Table 1). In a subset of patients, to chemotherapy or radiation therapy. the cause remains unknown despite laboratory N 2 About 60% of cancer patients experience nausea and radiologic investigations. and 30% vomiting.1–3 Both are distressing, cause significant morbidity, and reduce quality of life. History Nausea and vomiting contribute significantly to An important part of assessing nausea and vom- nutritional deterioration and increased pain inten- iting is a detailed history (Table 2). The history sity. Patients dread nausea more than pain while provides clues as to causes which will direct drug physicians focus more on emesis than nausea. management. Nausea, an uncomfortable feeling of the need Pathophysiology/etiology to vomit, is associated with autonomic symptoms There are multiple causes of nausea and vomit- (pallor, cold sweats, tachycardia, and diarrhea). ing including gastrointestinal (GI), central ner- Vomiting, forceful expulsion of gastric contents results from relaxation of the stomach, esophageal Manuscript received July 26, 2012; accepted October 4, 2012. sphincter and pylorus with simultaneous contrac- Correspondence Mellar Davis, MP, MD, FCCP, FAAHPM, The Harry R. Horvitz Center for Palliative Med- tion of the abdominal muscles, and retroperistalsis icine, Section of Palliative Medicine and Supportive Oncology, from the small bowel. Vomiting is a brainstem Department of Solid Tumor Oncology, Cleveland Clinic response, whereas nausea is a cerebral sensation. Taussig Cancer Institute, 9500 Euclid Avenue, M77, Cleve- land, OH 44195 ([email protected]). Vomiting pathways are well characterized (through Disclosures The authors have completed the ICMJE Form animal studies) whereas little is known about the for Potential Conflicts on Interest. Dr Davis’ institution has neuroanatomy of nausea. Retching, a rhythmic received a grant from Pfizer for a fatigue study. Dr Davis has received payment for service on a speaker’s bureau from Ar- spasmodic movement of the diaphragm and ab- chimedes. dominal muscles without gastric content expul- 1 J Support Oncol 2013;11:8–13 © 2013 Frontline Medical Communications sion, is frequently classified as vomit.

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colic, change in bowel habit, early satiety and/or stool TABLE 1 Pathophysiology of nausea and vomiting consistency.4 Radiation to the abdomen, which also oc- Etiology Causes curs when one radiates the thoracic or lumbosacral spine, 5 Gastrointestinal Bowel Obstruction is emetogenic. In advanced cancer, autonomic failure is Gastroparesis common and may result in gastroparesis, nausea, vomiting and constipation.6 Pseudo-obstruction occurs from Ulceration paraneoplastic dysfunction of gastrointestinal smooth Constipation muscle or enteric neurons.7 Toxic megacolon and typhlitis Peritoneal Carcinomatosis may also resemble a bowel obstruction.8–9 It is important Typhlitis etc to recognize these last 2 disorders since management is Central Nervous System Increased Intracranial Pressure distinctly different; and both disorders are associated with Tumors catastrophic complications. Hydrocephalus Movement-related nausea is often associated with Hemorrhage vestibular dysfunction, but also occurs with mesenteric 10 Vestibular traction from peritoneal metastases. Early morning Metabolic Hypercalcemia etc occipital headaches and/or recent onset of neurologic Medication deﬁcits, focal neurologic signs and altered cognition on Psychiatric Anxiety physical examination suggests elevated intracranial Depression etc pressure from a posterior fossa tumor or central nervous system metastases.11–13 Brain imaging is indicated if one is suspicious of brain metastases, leptomeningeal carcinomatosis, strokes, subdural hematoma or intra- cerebral bleed. Persistent nausea unrelieved by vomit- TABLE 2 Characteristics of nausea/vomiting ing occurs more often from drug or metabolic causes.14

Characteristic Patients with nausea and altered sensorium should also be suspected of having a metabolic abnormality such as Quality Nausea, vomiting, retching, regurgitation hypercalcemia, hyponatremia, or uremia. Polyuria and Duration Over months or acutely polydipsia are common with diabetes insipidus, hypercalcemia or hyperglycemia.3 Character Persistent or intermittent Adrenal insufficiency occurs when the metastases Intensity Low grade, able to eat or precludes eating destroys both adrenal glands or from inadvertent dis- Nature of vomitus number Large volume, fecal like continuation of corticosteroids or high-dose progester- of episodes one. Primary adrenal insufficiency presents with hy- Associated symptoms Pain, altered bowel habit, perkalemia, hyponatremia and hypotension. Nausea, headache, colic occasional vomiting, abdominal pain or diarrhea that Aggravating factors Sight/smell of food, worse alternates with constipation, are common and correlate after eating, moving with severity of primary adrenal insufficiency. Vomit- Relieving factors Medications, over-the-counter ing and abdominal pain often herald adrenal crisis, and remedies, alternative nonpharmacologic measures loss of fluid due to vomiting or diarrhea may precipitate Temporal factors Relation of vomiting to nausea the crisis. Drug history Opioid, nonsteroidal anti- Medications are reviewed with the initial history and inflammatory drugs should include over-the-counter medications. Comple- Recent anticancer Within the week, during mentary therapies, including herbs and vitamins, may or treatment radiation may not be volunteered and are commonly used in our population. Removing the offending drugs will avoid antiemetics and drug-drug interactions.3 Patients should be screened for depression and anxiety as causes of psycho- Patterns of nausea and vomiting provide clues.2 Nau- genic nausea. sea relieved by vomiting is likely to be generated by gastrointestinal pathology. Nausea and vomiting from Physical examination bowel obstruction, gastric outlet obstruction or stasis is The physical examination is commonly unremarkable; commonly accompanied by abdominal pain, bloating, however, certain findings are helpful in uncovering the

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underlying cause.3 Candidiasis, mucosal ulceration, vesic- vomiting. A computed tomography (CT) scan of the ular oral herpetic lesions are clues to treatable gastroin- abdomen and pelvis provides additional diagnostic intestinal causes of nausea and dysphagia. Pertinent abdom- formation (eg, the presence of peritoneal carcinomato- inal findings are hepatomegaly, splenomegaly, and ascites. sis, site or sites of obstruction, extent of intra- A succussion splash suggests impaired gastric emptying or abdominal cancer, location of bowel obstruction, and gastric outlet obstruction.15,16 The sign will be lost if the whether or not palliative surgical intervention is an patient has recently vomited. A “Sister Mary Joseph” option). Magnetic resonance imaging (MRI) of the node, a palpable periumbilical node, may be found with abdomen and ultrasounds are rarely done but could advanced intra-abdominal carcinoma.17 A rectal exami- substitute for CT scans in those who cannot take oral nation is important to assess for sphincter tone, fecal contrast.24 Gastrografin enemas are used to look for impaction and possible pelvic malignancy. A “Blumer’s colonic obstruction and may also relieve intractable shelf”, a rim of tumor felt during the rectal examination, constipation.25 We order an MRI of the brain in those is found with advanced abdominal or non-abdominal can- whose history and physical examination suggests a cen- cers with “drop” metastases or in pelvic cancers with local tral neurologic etiology (eg, intractable nausea, vomit- infiltration.18 Bowel sounds may be helpful if they are ing, and/or new neurological deficits). When a patient hyperactive, high pitched or if borborygmi is heard sug- is terminally ill or imminently dying, decisions to in- gesting small bowel or colonic obstruction.18 Most upper tervene are complicated and need to be based on pa- abdominal obstructions produce greater symptoms than tient/family goals of care and the risks and benefits of lower abdominal obstructions which, in our experience, the intervention. seem to produce more signs than symptoms. Papilledema though rare, occurs with increased intracranial pres- Interventions 3,19 sure. Fever and confusion of rapid onset are signs of We routinely use single agents in a sequential fashion sepsis and metabolic abnormalities (liver failure, renal based upon response; and, on occasion, we use drug com- failure, and hypercalcemia). binations for refractory nausea. Several drug classes are effective as antiemetics and offer some versatility, such as Investigations multiple routes of administration.26 After a detailed history and physical examination, further investigations will depend on the goals of care, the pa- Management tient’s condition, and prognosis. Any identifiable, reversible cause is treated first. All med- Laboratory. A metabolic panel which includes so- ications are reviewed and non-essential medications dium, potassium, calcium, blood urea nitrogen, creati- (digoxin, statins, iron, etc) are discontinued. Patients may nine, and albumin screens for most metabolic abnormal- also receive standard antiemetics such as metoclopramide ities and is also helpful for assessing complications related or haloperidol to treat nausea and vomiting. Opioids are to nausea and vomiting. Persistent vomiting will produce rotated if one appears to be the offending agent despite azotemia which is largely prerenal, and often associated standard antiemetics. Suppositories, enemas and/or man- with hyponatremia. Hyponatremia will need to be differ- ual disimpaction are required in patients with fecal im- entiated from the syndrome of inappropriate antidiuretic paction. Bisacodyl suppositories have a dual action of hormone (SIADH). Elevated blood urea nitrogen, hyper- mechanical and chemical colonic stimulation. Enemas are uricemia and low urinary sodium content is frequently only used as rescue measures. Cotton seed enemas soften observed.20–22 SIADH is a diagnosis of exclusion but a hard stool and help relieve a hard impaction. Docusate must fulfill the 5 diagnostic criteria: (1) hyponatremia and magnesia hydroxide is used in the initial management with hypotonicity of plasma; (2) high urine osmolality of constipation.27 For individuals who failed to respond to relative to plasma osmolality; (3) increased renal sodium standard laxatives, cotton seed oil enemas and methyln- excretion; (4) absence of edema or evidence of volume altrexone is used. We infrequently use senna since it depletion; and (5) normal renal and adrenal function. causes significant cramps. Hypercalcemia, common in Measuring arginine vasopressin (AVP) levels is not par- multiple myeloma, squamous cancers and breast cancers is ticularly helpful in diagnosing SIADH. treated with hydration, bisphosphonates, and salmon cal- Radiology. To screen for ileus, constipation or bowel citonin for the first 48 to 72 hours. Salmon calcitonin is obstruction, we recommend a plain x-ray of the abdo- used for individuals who are experiencing complications men (also called kidneys ureter and bladder x-ray related to hypercalcemia including azotemia, confusion or [KUB]).23 The abdominal plain x-ray is helpful in sedation. If refractory, gallium nitrate has been used. managing patients with constipation and nausea and Monthly bisphosphonates are ordered to prevent recur-

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Bowel obstruction Malignant bowel obstruction requires a highly individualized approach, tailored to the particular medical situa- tion, prognosis, and goals of care.35 Each symptom pres- ent may require a different approach and drug class.35 As an example, metoclopramide has been effective in partial small bowel obstruction and ileus but may worsen nausea, vomiting, and the pain of a complete mechanical obstruction. Worsening colic and nausea and vomiting on metoclopramide may be an indication of an evolving complete bowel obstruction. Partial bowel obstruction and FIGURE 1 Causes and proposed mechanisms of nausea and vom- ileus may respond to parenteral metoclopramide. Many iting. malignant obstructions are partial. Opioids relieve the continuous abdominal pain from peritoneal implants and rent hypercalcemia in those who have months to survive; retroperitoneal invasion but can aggravate colic by stim- but they are discontinued when a patient enters hospice, ulating circular smooth muscles, increasing segmental 36 has rapidly advancing disease, is imminently dying, or contractions. Opioid-sparing adjuvant drugs (ie, ke- whose goals are care and comfort. torolac or corticosteroids) may improve colic, lessen con- Treatment of nausea and vomiting at the Cleveland tinuous pain, and prevent a partial obstruction from be- 37 Clinic, Harry R Horvitz Center for Palliative Medicine coming complete. Nausea and vomiting from bowel inpatient unit consists of metoclopramide or haloperi- obstruction frequently requires both antisecretory and an- dol as first-line treatment, olanzapine or chlorproma- ticholinergic drugs (octreotide and glycopyrrolate) which 38–39 zine as second-line treatment, and ondansetron as reduce GI secretions and distention as well as colic. third-line therapy. Little is known about pathways that In addition, a low-residue diet often called a gastrointes- generate nausea which tends to respond less well to tinal soft diet should be used to prevent a complete bowel 40 antiemetics. Some approach the management of nausea obstruction. The combination of an anticholinergic plus and vomiting based upon “emetogenic receptor path- octreotide reduces nausea and vomiting in those individ- ways” to select agents.14,28 We have not used these uals who failed to respond to either agent alone.41 Gly- empiric-based guidelines, but have chosen to use se- copyrrolate, morphine, octreotide and haloperidol are quential single-agent therapy. There is little evidence compatible in a solution and can be combined.39 These that an antiemetic choice based upon emetogenic re- agents can be administered intravenously (IV) or subcu- ceptor pathways is any better than empiric single-agent taneously (SC), and hydration if needed can be given IV therapy (Figure 1).26 or by hypodermoclysis. Octreotide is well tolerated, re- Metoclopramide and haloperidol are antiemetics of duces the need for a nasogastric tube insertion without choice as first-line agents (Figure 2). Metoclopramide resulting in severe xerostomia (unlike anticholinergics). has the greatest evidence for efficacy in advanced can- Some patients prefer octreotide rather than an anticho- cer.26 Both dexamethasone and 5HT3 receptor antag- linergic.42 However, the high cost of octreotide limits its onists (ie, ondansetron) are recommended for vomiting use in American hospices due to the Medicare capitation from abdominal and chest radiation. Abdominal para- system of reimbursement; therefore, we use octreotide as centesis relieves nausea associated with ascites. Dexa- a second-tier drug. Octreotide doses are 100 to 200 ␮g methasone for cerebral edema is our treatment of every 8 hours.10 Total daily doses as high as 900 ␮g/day choice for intracranial tumors. Promethazine, owing to are reported.42 its anticholinergic and antihistaminic action is helpful A partial small-bowel obstruction or ileus may respond for vertigo and is occasionally used though scopolamine to metoclopramide. Metoclopramide has a short half life. is our preferred choice.29 Radiation therapy can palliate Doses are 10 mg before meals and at bedtime. We also cranial metastasis and leptomeningeal cancer. Anti- give this parenterally either IV or SC starting with doses seizure medications such as gabapentin and carbamaz- of 40–60 mg daily and titrating to 120 mg per day. epine may reduce nausea and vomiting from a variety of Patients who have not responded to 120 mg per day are causes, including leptomeningeal disease with gabap- switched to haloperidol, chlorpromazine or olanzapine. entin being the preferred agent due to fewer drug Initial haloperidol doses are 1 mg twice a day and as interactions.29–34 We have had only anecdotal experi- needed every 4 hours by mouth. For those who require ence with leptomeningeal metastases. parenteral haloperidol, 5 mg is given IV or SC over 24

Volume 11/Number 1 March 2013 Ⅲ THE JOURNAL OF SUPPORTIVE ONCOLOGY 11 How We Do It

Search for Reversible Causes

Flat Plate X -ray of Abdomen

Dexamethasone if CNS Metoclopramide Enema if malignancy PO: 10mg AC and HS constipation 8mg PO/IV/SC at 8am and 12noon IV/SC: 40

If bowel obstruction, Haloperidol haloperidol + glycopyrrolate PO: 1mg q 12h, 0.2mg IV/SC q 6 h IV/SC: 5mg/24hours

Dexamethasone Olanzapine Octreotide IV/SC: 8mg q 8am SL: 2.5-5mg q 12 h, 2.5-5mg IV/SC: 100mcg q 8h & noon

Chlorpromazine PO: 12.5 q 6h, 12.5 Q 6h PRN Dexamethasone IV/SC: 8mg q 8am & noon Ondansetron PO: 4-8mg BID & q 6 h PRN

FIGURE 2 The cleveland clinic approach to managing nausea and vomiting in a palliative inpatient unit.

hours with a rescue dose of 1 mg every 4 hours as needed. inhibitor, or stenting.45 For patients with poor perfor- There is a concern for the “black box” warning about mance status, progressive disease, peritoneal carcino- prolonged repolarization (prolonged QTc interval) with matosis, life expectancy of days to weeks, or multiple haloperidol. We have not routinely obtained electrocar- levels of obstruction, a venting percutaneous endo- diograms since most of our patients are terminally ill with scopic gastrostomy (PEG) tube is considered if maxi- few options. Chlorpromazine doses are 12.5 mg IV every mum medical therapy is ineffective or if the patient is 4 hours as needed and titrated to response which can be going home with hospice. Symptoms of malignant gas- as high as 100 mg every 4 hours. Sedation can be an issue trointestinal obstruction that improve with a nasogas- with chlorpromazine. Olanzapine doses are 5 mg as a tric tube predicts the benefits of a “venting” PEG tube. dissolvable disc at night and every 6 hours as needed. PEG tube drainage reduces drug costs and potential Twice-daily doses as high as 10 mg have been used in readmissions which is important in hospice. chemotherapy-related nausea and vomiting. Olanzapine has been reported to be well absorbed SC; hence, this is Conclusion the route that we prefer for those who are unable to take it by mouth.43 Ondansetron is a third-line agent. Dosing Patterns of nausea and vomiting are helpful. Based on our for ondansetron is 4 to 8 mg oral twice a day and 4 mg experience, empiric single-drug therapy is as effective as every 6 hours as needed. Dexamethasone 8 mg oral/ antiemetic choices based on mechanism. Metoclopramide IV/SC at 8 am and noon is our standard dosing schedule. has the greatest evidence for benefit and hence is our We rarely use a cannabinoid.44 first-line treatment in those who have not been on metoclopramide before. Haloperidol is also used particularly Nonpharmacologic intervention in the face of a complete bowel obstruction. Second-line In our experience, when a patient’s nausea and vomit- agents used by our institution are the atypical antipsy- ing persists despite standard antiemetics, the patient chotic, olanzapine, phenothiazine, or chlorpromazine. should be evaluated for CNS metastases, achalasia from Antiemetic rotation, titration, antiemetic combinations tumor infiltration in the lower esophageal sphincter, with complementary receptor activities have low levels of gastritis, linitis plastica, gastric ulcer or strictures. evidence in managing refractory nausea. Nonpharmaco- These causes for nausea and vomiting may respond to logic approaches should be used depending on the clinical a botulin toxin injection, dilatation, a proton pump circumstance and patient prognosis.

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Acknowledgment obstruction: a prospective study of 117 cases. Br J Surg. 1984; The Harry R. Horvitz Center for Palliative Medicine is a World Health 71(10):799-801. Organizati/on Demonstration Project and ESMO designated Palliative 26. Davis MP, Hallerberg G; Palliative Medicine Study Group of the Program. (www.clevelandclinic.org/palliative). Multinational Association of Supportive Care in Cancer. A system- Previous Presentation: Presented in part at the Seventh Annual Chi- atic review of the treatment of nausea and/or vomiting in cancer cago Supportive Oncology Conference; October 27-29, 2011; Illinois. unrelated to chemotherapy or radiation. J Pain Symptom Manage. 2010;39(4):756-767. References 27. Davis MP. The opioid bowel syndrome: a review of pathophysiol- 1. Reuben DB, Mor V. Nausea and vomiting in terminal cancer ogy and treatment. J Opioid Manag. 2005;1(3):153-161. patients. Arch Intern Med. 1986;146(10):2021-2023. 28. Stephenson J, Davies A. 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Arch Dermatol. 1992; lignant chronic abdominal pain and malignant bowel obstruction. 128(4):548-549,551-552. Gastroenterol Clin North Am. 2006;35(1):131-142. 17. Winne BURCHARD BE. Blumer’s shelf tumor with primary car- 39. Davis MP, Furste A. Glycopyrrolate: a useful drug in the palliation cinoma of the lung. A case report. J Int Coll Surg. 1965;44(5):477- of mechanical bowel obstruction. J Pain Symptom Manage. 1999; 481. 18(3):153-154. 18. Gu Y, Lim HJ, Moser MA. How useful are bowel sounds in 40. McCallum P, Walsh D, Nelson KA. Can a soft diet prevent bowel assessing the abdomen? Dig Surg. 2010;27(5):422-426. obstruction in advanced pancreatic cancer? Support Care Cancer. 19. Rath S, Das BS, Kar C, et al. Intracranial space occupying lesions 2002;10(2):174-175. presenting without papilloedema—a retrospective analysis. Neurol India. 1978;26(3):140-143. 41. Mercadante S. Scopolamine butylbromide plus octreotide in unre- 20. Suhardjono. Hyponatremia, prevalence, diagnosis, and manage- sponsive bowel obstruction. J Pain Symptom Manage. 1998;16(5): ment. Acta Med Indones. 2011;43(3):149-151. 278-280. 21. Raftopoulos H. Diagnosis and management of hyponatremia in 42. Mercadante S, Porzio G. Octreotide for malignant bowel obstruc- cancer patients. Support Care Cancer. 2007;15(12):1341-1347. tion: Twenty years after. Crit Rev Oncol Hematol. 2012;83(3);388- 22. McDonald GA, Dubose TD Jr. Hyponatremia in the cancer pa- 392. tient. Oncology (Williston Park). 1993;7(9):55-64; discussion 67-68; 43. Elsayem A, Bush SH, Munsell MF, et al. Subcutaneous olanzapine 70-71. for hyperactive or mixed delirium in patients with advanced cancer: 23. Starreveld JS, Pols MA, Van Wijk HJ, et al. The plain abdominal a preliminary study. J Pain Symptom Manage. 2010;40(5):774-782. radiograph in the assessment of constipation. Z Gastroenterol. 1990; 44. Gonzalez-Rosales F, Walsh D. Intractable nausea and vomiting due 28(7):335-338. to gastrointestinal mucosal metastases relieved by tetrahydrocan- 24. Chou CK, Liu GC, Chen LT, et al. The use of MRI in bowel nabinol (dronabinol). J Pain Symptom Manage. 1997;14(5):311-314. obstruction. Abdom Imaging. 1993;18(2):131-135. 45. Brücher BL, Stein HJ, Bartels H, et al. Achalasia and esophageal 25. Stewart J, Finan PJ, Courtney DF, et al. Does a water soluble cancer: incidence, prevalence, and prognosis. World J Surg. 2001; contrast enema assist in the management of acute large bowel 25(6):745-749.

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