Treatment-Associated Nausea and Vomiting: A Review of Guidelines

Most patients undergoing anticancer chemotherapy or radiation therapy will experience treatment-induced nausea and vomiting. But key gaps remain in our understanding of how best to prevent and treat this debilitating adverse effect, leading to inconsistencies among clinical antiemetic guidelines. The available evidence for how best to prevent and manage nausea and vomiting during and following radiotherapy is particularly scant, precluding a comprehensive evidence-based consensus.

This article presents a review of the biologic pathways and treatment risk categories for chemotherapy-induced nausea and vomiting (CINV) and radiotherapy-induced nausea and vomiting (RINV), areas of consensus in the clinical guidelines from the American Society of Clinical Oncology (ASCO), the Multinational Association for Supportive Care in Cancer (MASCC) and European Society of Clinical Oncology (ESMO), and the National Comprehensive Cancer Network (NCCN) for preventing and managing CINV and RINV, and key evidence gaps for which additional research is urgently needed. Barriers to the effective implementation of guidelines are also described.

Chemotherapy- and radiotherapy-induced nausea and vomiting are common adverse events during cancer therapy, affecting most patients at some point during or following treatment.^1-3 For example, 50% to 80% of patients undergoing radiotherapy for cancer will experience RINV.³ Surprisingly, given this ubiquity, the prevention and management of these debilitating conditions has been relatively little studied in large, randomized, controlled prospective clinical trials.^2,3 RINV, in particular, is underreported and has been under-researched.³ The resulting evidence gaps have contributed to differences in clinical guidelines’ recommendations for the prevention of CINV and RINV in certain patient populations and for the optimal management of breakthrough RINV.^2,3

Causes and Triggers

The biology of CINV and RINV are not completely understood. Nausea and vomiting are distinct, highly evolutionarily conserved biological mechanisms among vertebrates and are viewed as evolved adaptations for avoiding the harms caused by ingestion or inhalation of poisonous or infected substances. Nausea involves autonomic nervous system pathways, whereas vomiting is a highly coordinated muscular activity controlled by the brain in response to stress, pain, smells, or tastes.¹

The brain’s medulla oblongata harbors a chemoreceptor trigger zone of nerves receiving signals from the circulatory system that can trigger CINV in response to the presence of circulating chemotherapy agents.¹ Sympathetic nerve signals indicative of noxious chemicals in the internal organs or acute inflammation also trigger vomiting.¹ The neurotransmitters dopamine, serotonin (5-HT), neurokinin 1 (NK₁), and substance P are involved in CINV- and RINV-triggering biological pathways and have each, therefore, been targeted in the development of antiemetic agents.¹

Categorizing Emetogenicity

CINV or RINV episodes that occur within 24 hours of administration or exposure are considered acute, whereas delayed CINV and RINV occur more than 24 hours after treatment exposure.¹ Psychosomatic anticipatory CINV and RINV also occur in a minority (up to 8%) of patients undergoing cancer treatment, particularly among those with previous exposure to emetogenic treatments.⁵

Different cancer treatment regimens carry different risks for acute or delayed nausea and vomiting. ASCO and the US National Cancer Institute (NCI) define highly emetogenic therapies as those that trigger nausea and vomiting in 90% or more of patients, whereas low-emetogenic and minimally emetogenic therapies trigger nausea and vomiting in 10% to 30% and less than 10% of patients, respectively.^1-3,6 The severity of acute, late, or anticipatory nausea and vomiting is described using toxicity grades, as with other adverse effects of cancer therapy (Table 1).

TABLE 1. NCI CTCAE: Nausea and Vomiting^1,7

Adverse Event	Grade	Description
Nausea	1	Loss of appetite without alteration in eating habits
	2	Oral intake decreased without significant weight loss, dehydration, or malnutrition
	3	Inadequate oral caloric or fluid intake Tube feeding, TPN, or hospitalization indicated
Vomiting	1	1-2 episodes (separated by 5 min) in 24 h
	2	3-5 episodes (separated by 5 min) in 24 h
	3	≥6 episodes (separated by 5 min) in 24 h Tube feeding, TPN, or hospitalization indicated
	4	Life-threatening consequences Urgent intervention indicated
	5	Death
Key: CTCAE, Common Terminology Criteria for Adverse Events; NCI, National Cancer Institute; TPN, total parenteral nutrition.

Generally, highly emetogenic chemotherapy includes high-dose cisplatin, carmustine, cyclophosphamide (at doses exceeding 1500 g/m²), dacarbazine, mechlorethamine, streptozocin, and anthracycline- and cyclophosphamide-based regimens.² Moderately emetogenic chemotherapies include carboplatin, doxorubicin, irinotecan, oxaliplatin, and lower-dose cyclophosphamide regimens.² Immunotherapies, targeted agents, docetaxel, pemetrexed, and eribulin are considered low-emetogenic treatments.² (Some targeted and immunotherapeutic agents are considered minimally emetogenic. These include nivolumab, pembrolizumab, trastuzumab, and bevacizumab.²)

Emetogenicity of radiotherapy varies primarily with the irradiated anatomy: total body irradiation is highly emetogenic, causing RINV in 90% of patients, whereas craniospinal and upper body and abdominal (upper abdominal) radiotherapy are considered moderately emetogenic, causing RINV in 30% to 90% of patients.³ Central nervous system (CNS), head and neck, thoracic, and pelvic radiotherapy carry a low risk (less than 30%) of RINV, and limb and breast radiotherapy carry minimal (less than 10%) emetogenic risk.³

Consensus and Inconsistencies

ASCO, MASCC/ESMO, and NCCN have all produced clinical antiemetic guidelines for RINV and CINV.^6,8,9 A recent review of the clinical guidelines for the prevention and treatment of CINV concluded that the MASCC/ESMO, ASCO, and NCCN guidelines offer “a relatively high degree of concordance” overall — with the ASCO and NCCN guidelines being most similar — and noted that some of the differences between these guidelines are due to an evolving evidence base between their publications (in 2016, 2017, and 2018, respectively).²

Chemotherapy-induced nausea and vomiting Recommendations for CINV prevention and treatment vary both between guidelines and by the emetogenic risks of the regimen. For prophylaxis among patients receiving highly emetogenic chemotherapy, ASCO recommends a 4-drug regimen of 5-HT3 receptor antagonist (RA), NK₁ RA, olanzapine, and dexamethasone.²

For moderately emetogenic regimens, ASCO and MASCC/ESMO both recommend 2-drug prophylactic regimens (5-HT3 RA plus dexamethasone) plus an NK₁ RA for patients receiving carboplatin at doses of or exceeding an area under the curve (AUC) dose of 4 mg/mL per minute.²

NCCN recommendations offer 3 antiemetic dosing options, each includes dexamethasone and a 5-HT3 RA for acute cases. One NCCN option for acute-onset CINV specifies palonosetron as the 5-HT3 RA, and another includes an NK₁ RA.^2,9

For low-emetogenic risk chemotherapy regimens, acute CINV is treated with either dexamethasone or a 5-HT3 RA under the ASCO guideline; or dexamethasone, metoclopramide, prochlorperazine, or a 5-HT3 RA under the NCCN guideline; or a 5-HT3 RA, dexamethasone, or dopamine RA under the MASCC/ESMO antiemetic guideline.^2,6,8,9 None of the guidelines offer recommendations for minimally emetogenic chemotherapy regimens.²

MASCC/ESMO recommendations include aprepitant treatment for delayed CINV among patients taking carboplatin-based chemotherapy regimens; the ASCO guidelines offer no specific recommendations for these cases.²

Radiotherapy-induced nausea and vomiting A separate comparison of the ASCO, NCCN, and MASCC/ESMO clinical guidelines’ recommendations for the prevention and treatment of RINV came to a similar conclusion, noting differences between the guidelines in their recommendations for preventing or treating RINV in patients undergoing low-risk and minimal-risk treatments, breakthrough RINV, and for patients undergoing concomitant chemoradiation therapy.³

For example, whereas the MASCC/ESMO and ASCO guidelines recommend employing CINV regimen antiemetic prophylaxis for patients undergoing chemoradiation, the NCCN guideline authors made no specific recommendations for antiemetic prophylaxis among patients undergoing concomitant chemoradiation.^3,6,8,9 And whereas NCCN’s guideline recommends that patients who experience breakthrough RINV be treated similarly to patients with breakthrough CINV, with a different class of antiemetic therapy, or with the 5-HT3 RA ondansetron or granisetron; the ASCO and MASCC/ESMO guidelines do not address breakthrough RINV.^3,6,8,9

NCCN does not make recommendations for treating low- or minimal-emetogenic-risk radiotherapy, whereas the other guidelines recommend 5-HT3 RA, dopamine receptor antagonists (DRAs), or dexamethasone for prophylaxis and rescue antiemesis for low-risk radiotherapy and 5-HT3 RA, DRA, or dexamethasone for rescue.^3,6,8,9

For patients at high risk of RINV, all 3 guidelines recommend prophylaxis with a 5-HT3 RA and dexamethasone or optional dexamethasone.^3,6,8,9 For patients at moderate risk of RINV, the 3 guidelines recommend varying regimens of prophylactic 5-HT3 RA and dexamethasone.^3,6,8,9

More research is needed for optimal anti-RINV regimens and antiemetic dosing schedules, particularly for patients undergoing low- and minimal-emetogenic risk radiotherapy and for how best to treat breakthrough RINV.³