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Published in: Supportive Care in Cancer 1/2017

01-01-2017 | Special Article

2016 Updated MASCC/ESMO consensus recommendations: Management of nausea and vomiting in advanced cancer

Authors: Declan Walsh, Mellar Davis, Carla Ripamonti, Eduardo Bruera, Andrew Davies, Alex Molassiotis

Published in: Supportive Care in Cancer | Issue 1/2017

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Abstract

Purpose

The aim of this paper is to review the existing literature related to the management of nausea and vomiting (N & V) in advanced cancer and derive clinical evidence-based recommendations for its management.

Methods

Available systematic reviews on antiemetic drug effectiveness were used. One generic systematic review of antiemetics in advanced cancer (to 2009) was updated to February 2016. Agreement on recommendations was reached between panel members, and these were voted in favor unanimously by the larger antiemetic committee membership (n = 37).

Results

The evidence base in this field is minimal with largely poor quality trials or uncontrolled trials and case studies. The level of evidence in most studies is low. The drug of choice for managing N & V in advanced cancer is metoclopramide titrated to effect. Alternative options include haloperidol, levomepromazine, or olanzapine. For bowel obstruction, the recommendation is to use octreotide given alongside an antiemetic (haloperidol) and where octreotide is not an option to use an anticholinergic antisecretory agent. For opioid-induced N & V, no recommendation could be made.

Conclusion

These new guidelines, based on the existing (but poor) evidence, could help clinicians manage more effectively the complex and challenging symptoms of N & V in advanced cancer.
Literature
2.
go back to reference Conill C, Verger E, Henriquez I, Saiz N, Espier M, Lugo F, Garrigos A (1997) Symptom prevalence in the last week of life. J. Pain Symptom Manag 14:328–331CrossRef Conill C, Verger E, Henriquez I, Saiz N, Espier M, Lugo F, Garrigos A (1997) Symptom prevalence in the last week of life. J. Pain Symptom Manag 14:328–331CrossRef
4.
go back to reference Bentley A, Boyd K (2001) Use of clinical pictures in the management of nausea and vomiting: a prospective audit. Palliat Med 15(3):247–253CrossRefPubMed Bentley A, Boyd K (2001) Use of clinical pictures in the management of nausea and vomiting: a prospective audit. Palliat Med 15(3):247–253CrossRefPubMed
5.
go back to reference Stephenson J, Davis A (2006) An assessment of aetiology-based guidelines for the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer 14:348–353CrossRefPubMed Stephenson J, Davis A (2006) An assessment of aetiology-based guidelines for the management of nausea and vomiting in patients with advanced cancer. Support Care Cancer 14:348–353CrossRefPubMed
6.
go back to reference Gupta M, Davis M, LeGrand S, Walsh D, Lagman R (2013) Nausea and vomiting in advanced cancer: the Cleveland Clinic protocol. J Support Oncol 11(1):8–13PubMed Gupta M, Davis M, LeGrand S, Walsh D, Lagman R (2013) Nausea and vomiting in advanced cancer: the Cleveland Clinic protocol. J Support Oncol 11(1):8–13PubMed
7.
go back to reference Davis MP, Hallerberg G, Palliative Medicine Study Group of the Multinational Association of Supportive Care in Cancer (2010) A systematic review of the treatment of nausea and/or vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manag 39(4):756–767CrossRef Davis MP, Hallerberg G, Palliative Medicine Study Group of the Multinational Association of Supportive Care in Cancer (2010) A systematic review of the treatment of nausea and/or vomiting in cancer unrelated to chemotherapy or radiation. J Pain Symptom Manag 39(4):756–767CrossRef
8.
go back to reference Dorman S, Perkins P (2010) Droperidol for treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev 6(10):CD006938–10.1002/14651858.CD006938.pub2 Dorman S, Perkins P (2010) Droperidol for treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev 6(10):CD006938–10.1002/14651858.CD006938.pub2
9.
go back to reference Storrar J, Hitchens M, Platt T, Dorman S (2014) Droperidol for treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev 11:CD006938 Storrar J, Hitchens M, Platt T, Dorman S (2014) Droperidol for treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev 11:CD006938
10.
go back to reference Perkins P, Dorman S (2009) Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev. 2009(2) Perkins P, Dorman S (2009) Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev. 2009(2)
11.
go back to reference Murray-Brown F, Dorman S (2015) Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev 11:CD006271 Murray-Brown F, Dorman S (2015) Haloperidol for the treatment of nausea and vomiting in palliative care patients. Cochrane Database Syst Rev 11:CD006271
12.
go back to reference Fletcher DS, Coyne PJ, Dodson PW, Parker GG, Wan W, Smith TJ (2014) A randomized trial of the effectiveness of topical “ABH Gel” (Ativan((R)), Benadryl((R)), Haldol((R))) vs. placebo in cancer patients with nausea. J Pain symptom manag 48(5):797–803CrossRef Fletcher DS, Coyne PJ, Dodson PW, Parker GG, Wan W, Smith TJ (2014) A randomized trial of the effectiveness of topical “ABH Gel” (Ativan((R)), Benadryl((R)), Haldol((R))) vs. placebo in cancer patients with nausea. J Pain symptom manag 48(5):797–803CrossRef
13.
go back to reference Hardy JR, O’Shea A, White C, Gilshenan K, Welch L, Douglas C (2010) The efficacy of haloperidol in the management of nausea and vomiting in patients with cancer. J Pain Symptom Manag 40(1):111–116CrossRef Hardy JR, O’Shea A, White C, Gilshenan K, Welch L, Douglas C (2010) The efficacy of haloperidol in the management of nausea and vomiting in patients with cancer. J Pain Symptom Manag 40(1):111–116CrossRef
14.
go back to reference Dietz I, Schmitz A, Lampey I, Schulz C (2013) Evidence for the use of levomepromazine for symptom control in the palliative care setting: a systematic review. BMC Palliat Care 12:2CrossRefPubMedPubMedCentral Dietz I, Schmitz A, Lampey I, Schulz C (2013) Evidence for the use of levomepromazine for symptom control in the palliative care setting: a systematic review. BMC Palliat Care 12:2CrossRefPubMedPubMedCentral
16.
go back to reference Cox L, Darvill E, Dorman S (2015) Levomepromazine for nausea and vomiting in palliative care. Cochrane Database Syst Rev 11:CD009420 Cox L, Darvill E, Dorman S (2015) Levomepromazine for nausea and vomiting in palliative care. Cochrane Database Syst Rev 11:CD009420
18.
go back to reference Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M (2008) Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol 6(3):119–124PubMed Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M (2008) Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol 6(3):119–124PubMed
19.
go back to reference Gonzalez-Rosales F, Walsh D (1997) Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). J Pain Symptom Manag 14(5):311–314CrossRef Gonzalez-Rosales F, Walsh D (1997) Intractable nausea and vomiting due to gastrointestinal mucosal metastases relieved by tetrahydrocannabinol (dronabinol). J Pain Symptom Manag 14(5):311–314CrossRef
20.
go back to reference Hernandez SL, Sheyner I, Stover KT, Stewart JT (2015) Dronabinol treatment of refractory nausea and vomiting related to peritoneal carcinomatosis. Am j Hospice Palliat Care 32(1):5–7CrossRef Hernandez SL, Sheyner I, Stover KT, Stewart JT (2015) Dronabinol treatment of refractory nausea and vomiting related to peritoneal carcinomatosis. Am j Hospice Palliat Care 32(1):5–7CrossRef
21.
go back to reference Bruera ED, MacEachern TJ, Spachynski KA et al (1994) Comparison of the efficacy, safety, and pharmacokinetics of controlled release and immediate release metoclopramide for the management of chronic nausea in patients with advanced cancer. Cancer 74(12):3204–3211CrossRefPubMed Bruera ED, MacEachern TJ, Spachynski KA et al (1994) Comparison of the efficacy, safety, and pharmacokinetics of controlled release and immediate release metoclopramide for the management of chronic nausea in patients with advanced cancer. Cancer 74(12):3204–3211CrossRefPubMed
22.
go back to reference Bruera E, Belzile M, Neumann C, Harsanyi Z, Babul N, Darke A (2000) A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manag 19(6):427–435CrossRef Bruera E, Belzile M, Neumann C, Harsanyi Z, Babul N, Darke A (2000) A double-blind, crossover study of controlled-release metoclopramide and placebo for the chronic nausea and dyspepsia of advanced cancer. J Pain Symptom Manag 19(6):427–435CrossRef
23.
go back to reference Bruera E, Moyano JR, Sala R et al (2004) Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manag 28(4):381–388CrossRef Bruera E, Moyano JR, Sala R et al (2004) Dexamethasone in addition to metoclopramide for chronic nausea in patients with advanced cancer: a randomized controlled trial. J Pain Symptom Manag 28(4):381–388CrossRef
24.
go back to reference Corli O, Cozzolino A, Battaiotto L (1995) Effectiveness of levosulpiride versus metoclopramide for nausea and vomiting in advanced cancer patients: a double-blind, randomized, crossover study. J Pain Symptom Manag 10(7):521–526CrossRef Corli O, Cozzolino A, Battaiotto L (1995) Effectiveness of levosulpiride versus metoclopramide for nausea and vomiting in advanced cancer patients: a double-blind, randomized, crossover study. J Pain Symptom Manag 10(7):521–526CrossRef
25.
go back to reference Mystakidou K, Befon S, Trifyllis J, Liossi C, Papadimitriou J (1997) Tropisetron versus metoclopramide in the control of emesis in far-advanced cancer. Oncologist 2(5):319–323PubMed Mystakidou K, Befon S, Trifyllis J, Liossi C, Papadimitriou J (1997) Tropisetron versus metoclopramide in the control of emesis in far-advanced cancer. Oncologist 2(5):319–323PubMed
26.
go back to reference Mystakidou K, Befon S, Liossi C, Vlachos L (1998) Comparison of the efficacy and safety of tropisetron, metoclopramide, and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer 83(6):1214–1223CrossRefPubMed Mystakidou K, Befon S, Liossi C, Vlachos L (1998) Comparison of the efficacy and safety of tropisetron, metoclopramide, and chlorpromazine in the treatment of emesis associated with far advanced cancer. Cancer 83(6):1214–1223CrossRefPubMed
27.
go back to reference Mystakidou K, Befon S, Liossi C, Vlachos L (1998) Comparison of tropisetron and chlorpromazine combinations in the control of nausea and vomiting of patients with advanced cancer. J Pain symptom Manag 15(3):176–184CrossRef Mystakidou K, Befon S, Liossi C, Vlachos L (1998) Comparison of tropisetron and chlorpromazine combinations in the control of nausea and vomiting of patients with advanced cancer. J Pain symptom Manag 15(3):176–184CrossRef
28.
go back to reference Imai K, Ikenaga M, Kodama T, Kanemura S, Tamura K, Morita T (2013) Sublingually administered scopolamine for nausea in terminally ill cancer patients. Support Care Cancer 21(10):2777–2781CrossRefPubMed Imai K, Ikenaga M, Kodama T, Kanemura S, Tamura K, Morita T (2013) Sublingually administered scopolamine for nausea in terminally ill cancer patients. Support Care Cancer 21(10):2777–2781CrossRefPubMed
29.
go back to reference LeGrand SB, Walsh D (2010) Scopolamine for cancer-related nausea and vomiting. J Pain Symptom Manag 40(1):136–141CrossRef LeGrand SB, Walsh D (2010) Scopolamine for cancer-related nausea and vomiting. J Pain Symptom Manag 40(1):136–141CrossRef
30.
go back to reference Kaneishi K, Nishimura K, Sakurai N, et al (2016) Use of olanzapine for the relief of nausea and vomiting in patients with advanced cancer: a multicenter survey in Japan. Support care cancer (in press). Kaneishi K, Nishimura K, Sakurai N, et al (2016) Use of olanzapine for the relief of nausea and vomiting in patients with advanced cancer: a multicenter survey in Japan. Support care cancer (in press).
31.
go back to reference MacKintosh D (2016) Olanzapine in the management of difficult to control nausea and vomiting in a palliative care population: a case series. J Palliat Med 19(1):87–90CrossRefPubMed MacKintosh D (2016) Olanzapine in the management of difficult to control nausea and vomiting in a palliative care population: a case series. J Palliat Med 19(1):87–90CrossRefPubMed
32.
go back to reference Atkinson SR (2014) Olanzapine for intractable nausea and vomiting in palliative care patients not receiving chemotherapy. J Palliat Med 17(5):503–504CrossRefPubMed Atkinson SR (2014) Olanzapine for intractable nausea and vomiting in palliative care patients not receiving chemotherapy. J Palliat Med 17(5):503–504CrossRefPubMed
33.
go back to reference Krouse RS (2007) The international conference on malignant bowel obstruction: a meeting of the minds to advance palliative care research. J Pain Symptom Manag 34:S1–S6CrossRef Krouse RS (2007) The international conference on malignant bowel obstruction: a meeting of the minds to advance palliative care research. J Pain Symptom Manag 34:S1–S6CrossRef
34.
go back to reference Ripamonti C, Gerders H, Easson AM. (2013). Bowel Obstruction. In: Principles and practice of Palliative Care and Supportive Oncology (Eds: Berger AM, Shuster JL, Von Roenn JH) 4 Ed. Lippincott Williams & wilkins; 15:193–209. Ripamonti C, Gerders H, Easson AM. (2013). Bowel Obstruction. In: Principles and practice of Palliative Care and Supportive Oncology (Eds: Berger AM, Shuster JL, Von Roenn JH) 4 Ed. Lippincott Williams & wilkins; 15:193–209.
35.
go back to reference Currow D, Quinn S, Agar M, Fazekas B, Hardy J, McCaffrey N et al (2015) Double-blind, placebo controlled, randomized trial of octreotide in malignant bowel obstruction. J Pain Symptom Manag 49(5):814–820CrossRef Currow D, Quinn S, Agar M, Fazekas B, Hardy J, McCaffrey N et al (2015) Double-blind, placebo controlled, randomized trial of octreotide in malignant bowel obstruction. J Pain Symptom Manag 49(5):814–820CrossRef
37.
go back to reference Laval G, Rousselot H, Toussaint-Martel S, Mayer F, Terrebonne E, Francois E et al (2012) SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction. Bull Cancer 99(2):E1–9PubMed Laval G, Rousselot H, Toussaint-Martel S, Mayer F, Terrebonne E, Francois E et al (2012) SALTO: a randomized, multicenter study assessing octreotide LAR in inoperable bowel obstruction. Bull Cancer 99(2):E1–9PubMed
38.
go back to reference Mariani P, Blumberg J, Landau A, Lebrun-Jezekova D, Botton E, Beatrix O et al (2012) Symptomatic treatment with lanreotide microparticles in inoperable bowel obstruction resulting from peritoneal carcinomatosis: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 30:4337–4343CrossRefPubMed Mariani P, Blumberg J, Landau A, Lebrun-Jezekova D, Botton E, Beatrix O et al (2012) Symptomatic treatment with lanreotide microparticles in inoperable bowel obstruction resulting from peritoneal carcinomatosis: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 30:4337–4343CrossRefPubMed
39.
go back to reference Mercadante S, Ripamonti C, Casuccio A, Zecca E, Groff L (2000) Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 8:188–191CrossRefPubMed Mercadante S, Ripamonti C, Casuccio A, Zecca E, Groff L (2000) Comparison of octreotide and hyoscine butylbromide in controlling gastrointestinal symptoms due to malignant inoperable bowel obstruction. Support Care Cancer 8:188–191CrossRefPubMed
40.
go back to reference Tuca A, Roca R, Sala C, Porta J, Serrano G, Gonzalez-Barboteo J (2009) Efficacy of granisetron in the antiemetic control of nonsurgical intestinal obstruction in advanced cancer: a phase II clinical trial. J Pain Symptom Manag 37(2):259–270CrossRef Tuca A, Roca R, Sala C, Porta J, Serrano G, Gonzalez-Barboteo J (2009) Efficacy of granisetron in the antiemetic control of nonsurgical intestinal obstruction in advanced cancer: a phase II clinical trial. J Pain Symptom Manag 37(2):259–270CrossRef
41.
go back to reference Hisanaga T, Shinjo T, Morita T, Nakajima N, Ikenaga M, Tanimizu M et al (2010) Multicenter prospective study on efficacy and safety of octreotide for inoperable malignant bowel obstruction. JPN J Clin Onc 40(8):739–745CrossRef Hisanaga T, Shinjo T, Morita T, Nakajima N, Ikenaga M, Tanimizu M et al (2010) Multicenter prospective study on efficacy and safety of octreotide for inoperable malignant bowel obstruction. JPN J Clin Onc 40(8):739–745CrossRef
42.
go back to reference Watari H, Hosaka M, Wakui Y, Nomura E, Hareyama H, Tanuma F et al (2012) A prospective study on the efficacy of octreotide in the management of malignant bowel obstruction in gynecologic cancer. Int J Gynecol Cancer 22(4):692–696CrossRefPubMed Watari H, Hosaka M, Wakui Y, Nomura E, Hareyama H, Tanuma F et al (2012) A prospective study on the efficacy of octreotide in the management of malignant bowel obstruction in gynecologic cancer. Int J Gynecol Cancer 22(4):692–696CrossRefPubMed
43.
go back to reference Kubota H, Taguchi K, Kobayashi D, Naruyama H, Hirose M, Fukuta K et al (2013) Clinical impact of palliative treatment using octreotide for inoperable malignant bowel obstruction caused by advanced urological cancer. Asian Pacific J. Cancer Pres 14:7107–7110 Kubota H, Taguchi K, Kobayashi D, Naruyama H, Hirose M, Fukuta K et al (2013) Clinical impact of palliative treatment using octreotide for inoperable malignant bowel obstruction caused by advanced urological cancer. Asian Pacific J. Cancer Pres 14:7107–7110
44.
go back to reference Kaneishi K, Kawabata M, Morita T (2012) Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manag 44:604–607CrossRef Kaneishi K, Kawabata M, Morita T (2012) Olanzapine for the relief of nausea in patients with advanced cancer and incomplete bowel obstruction. J Pain Symptom Manag 44:604–607CrossRef
45.
go back to reference Berger J, Lester P, Rodrigues L (2016) Medical therapy of malignant bowel obstruction with octreotide, dexamethasone and metoclopramide. Am J Hospice Palliat Med 33(4):407–410CrossRef Berger J, Lester P, Rodrigues L (2016) Medical therapy of malignant bowel obstruction with octreotide, dexamethasone and metoclopramide. Am J Hospice Palliat Med 33(4):407–410CrossRef
46.
go back to reference Weber C (2009) Malignant irreversible intestinal obstruction: the powerful association of octreotide to corticosteroids antiemetics and analgesics. Am J Hosp Palliat Med 26(2):84–88CrossRef Weber C (2009) Malignant irreversible intestinal obstruction: the powerful association of octreotide to corticosteroids antiemetics and analgesics. Am J Hosp Palliat Med 26(2):84–88CrossRef
47.
go back to reference Fallon MT, Cherny NI (2015) Opioid therapy: optimizing analgesic outcomes. In: Cherny NI, Fallon MT, Kaasa S, Portenoy RK, Currow DC (eds) Oxford Textbook of Palliative Medicine, 5th edn. Oxford University Press, Oxford, pp 525–559 Fallon MT, Cherny NI (2015) Opioid therapy: optimizing analgesic outcomes. In: Cherny NI, Fallon MT, Kaasa S, Portenoy RK, Currow DC (eds) Oxford Textbook of Palliative Medicine, 5th edn. Oxford University Press, Oxford, pp 525–559
48.
go back to reference Campora E, Merlini L, Pace M, Bruzzone M et al (1991) The incidence of narcotic-induced emesis. J Pain Symptom Manag 6(7):428–430CrossRef Campora E, Merlini L, Pace M, Bruzzone M et al (1991) The incidence of narcotic-induced emesis. J Pain Symptom Manag 6(7):428–430CrossRef
49.
go back to reference Twycross R, Wilcock A, Howard P (2014) Palliative care formulary, 5 edn. palliativedrugs.com Ltd, Nottingham Twycross R, Wilcock A, Howard P (2014) Palliative care formulary, 5 edn. palliativedrugs.com Ltd, Nottingham
50.
go back to reference Hardy J, Daly S, McQuade B et al (2002) A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 10(3):231–236CrossRefPubMed Hardy J, Daly S, McQuade B et al (2002) A double-blind, randomised, parallel group, multinational, multicentre study comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o. in the treatment of opioid-induced nausea and emesis in cancer patients. Support Care Cancer 10(3):231–236CrossRefPubMed
51.
go back to reference Laugsand EA, Kaasa S, Klepstad P (2011) Management of opioid-induced nausea and vomiting in cancer patients: systematic review and evidence-based recommendations. Palliat Med 25(5):442–53CrossRefPubMed Laugsand EA, Kaasa S, Klepstad P (2011) Management of opioid-induced nausea and vomiting in cancer patients: systematic review and evidence-based recommendations. Palliat Med 25(5):442–53CrossRefPubMed
52.
go back to reference Sweeney C, Bogan C (2009) Assessment and management of opioid side effects. In: Bruera E, Higginson IJ, Ripamonti C. von Gunten C. Textbook of Palliative Medicine. CRC Press, Taylor & Francis, FL, USA, pp 390–401 Sweeney C, Bogan C (2009) Assessment and management of opioid side effects. In: Bruera E, Higginson IJ, Ripamonti C. von Gunten C. Textbook of Palliative Medicine. CRC Press, Taylor & Francis, FL, USA, pp 390–401
Metadata
Title
2016 Updated MASCC/ESMO consensus recommendations: Management of nausea and vomiting in advanced cancer
Authors
Declan Walsh
Mellar Davis
Carla Ripamonti
Eduardo Bruera
Andrew Davies
Alex Molassiotis
Publication date
01-01-2017
Publisher
Springer Berlin Heidelberg
Published in
Supportive Care in Cancer / Issue 1/2017
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI
https://doi.org/10.1007/s00520-016-3371-3

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