Guidelines on Radiation- and Chemotherapy-Induced Nausea and Vomiting

Nausea and vomiting (N/V) is a common complication of cancer treatment and a common cause of anxiety and distress in patients, in some cases even prior to their first chemotherapy session. It is important for oncologist/hematologists and their teams to recognize the significance of N/V and to create a strategy to address it. Prevention of N/V is ideal. Once N/V occurs, every effort should be made to eliminate it, or at least to minimize it.[1]

Emesis can result from radiation therapy, chemotherapy, targeted treatment, or immunotherapy. The treatment team should review the potential emetogenic potential of each treatment regimen, based on published information. In addition, each patient should be individually assessed for this risk before the initiation of treatment and should be re-assessed regularly throughout treatment. The ability of an agent to cause immediate and delayed N/V should be reviewed, so that the administration of antiemetogenic agents can be timed appropriately. it is also important to review all medications that the patient is taking to check for possible drug interaction.

 The following organizations have released guidelines for the management of emesis resulting from treatment of cancer:

• National Comprehensive Cancer Network (NCCN)
• Multinational Association for Supportive Care in Cancer (MASCC)/European Society for Medical Oncology (ESMO)
• American Society of Clinical Oncology (ASCO)
• Oncology Nursing Society (ONS)

The NCCN, MASCC/ESMO, and ASCO guidelines include management recommendations for both chemotherapy-induced nausea and vomiting (CINV) and radiation-induced nausea and vomiting (RINV).[2, 3, 4] The ONS recommendations are limited to CINV.[5]

Treatment recommendations are based on four types of chemotherapy-induced nausea and vomiting (CINV), as follows:

• Acute: Onset of emesis within a few minutes to several hours after chemotherapy is administered and usually peaking in the first 4-6 hours
• Delayed: Onset of emesis more than 24 hours after chemotherapy is administered
• Anticipatory: Onset of emesis prior to chemotherapy administration as a conditioned response in patients who have experienced emesis during a previous cycle of chemotherapy
• Breakthrough/refractory: Emesis despite prophylactic/breakthrough medications

All the guidelines use the following system to classify chemotherapy agents into the following risk groups:

• High emetic risk: ≥90% or more of patients experience emesis
• Moderate emetic risk: 30% to 90% of patients experience emesis
• Low emetic risk: 10% to 30% of patients experience emesis
• Minimal emetic risk: < 10% of patients experience emesis

The MASCC/ESMO and ASCO risk ratings for individual chemotherapy agents are similar,[3] as are the NCCN risk ratings, although the NCCN list of agents is more extensive.[2] Single-agent cisplatin and the combination of an anthracycline and cyclophosphamide are rated at high risk by all three organizations.[2, 3, 4] ASCO and NCCN recommend that in patients receiving combination chemotherapy, antiemetic treatment should be determined according to the agent posing the greatest degree of emetic risk.[2, 4]

NCCN guidelines state that the best management of acute or delayed CINV is prevention; patients should be protected before receiving chemotherapy and for the full period of risk (up to 4 days) afterward. General recommendations for prevention are as follows[2] :

• Prevention of acute emesis should start before chemotherapy and continue for the first 24 hours
• Prevention of delayed emesis is a continuation of prophylactic treatment for 2 to 4 days following completion of chemotherapy
• Because breakthrough/refractory emesis is difficult to reverse, prevention using routine around-the-clock administration of antiemetics is preferred over as-needed (PRN) dosing
• Prevention is also key to the management of anticipatory emesis
• Relaxation/systematic desensitization, hypnosis with guided imagery, and music therapy are behavioral interventions that may be considered for anticipatory emesis; acupuncture/acupressure are additional options
• Consider using lorazepam as an adjuvant to the antiemetic regimen to decrease anxiety in patients at risk for anticipatory emesis
• Consider using an H2 blocker or a proton pump inhibitor to prevent dyspepsia
• Consider other potential causes of emesis in cancer patients (eg, bowel obstruction)

The NCCN recommends basing the choice of antiemetic(s) used on the emetic risk of the therapy, prior experience with antiemetics, and patient factors. Patient risk factors for anticancer agent–induced nausea/vomiting include the following:

• Younger age
• Female sex
• Previous history of CINV
• Little or no previous alcohol use
• Prone to motion sickness
• History of morning sickness during pregnancy
• Anxiety/high pretreatment expectation of nausea

Antiemetic agents

Neurokinin 1 receptor antagonist (NK1 RA):

• Aprepitant (APR) PO/IV
• Fosaprepitant (FOS)
• Netupitant/palonosetron (fixed NK1 RA and selective 5-hydroxytryptamine receptor antagonist [5-HT3 RA] combination)

 5-HT3 RA:

• Dolasetron
• Granisetron PO/IV/transdermal
• Ondansetron
• Palonosetron
• Dexamethasone (DEX) PO/IV
• Olanzapine PO - Off-label use for prevention of chemotherapy associated nausea or vomiting in combination with 5-HT3 antagonist and DEX ^[6]

Recommended antiemetic agents by emetic-risk categories are shown in the table below.

Table. Antiemetic Treatment Recommendations (Open Table in a new window)

Additional guidance

ASCO guidelines also include the following recommendations[4]

• Lorazepam is a useful adjunct to antiemetic drugs, but is not recommended as a single-agent antiemetic.
• Evidence remains insufficient for a recommendation for or against the use of ginger, acupuncture/acupressure, and other complementary or alternative therapies for the prevention of CINV.  
• Evidence remains insufficient for a recommendation regarding medical marijuana for the prevention of CINV, or for the use of medical marijuana in place of the US Food and Drug Administration–approved cannabinoids dronabinol and nabilone for treatment of CINV.
• Adult patients treated with high-dose chemotherapy and stem cell or bone marrow transplantation should be offered a three- drug combination of an NK1 RA, a 5-HT3 RA, and dexamethasone, or a four-drug combination of an NK1 receptor antagonist, a 5-HT3 receptor antagonist, dexamethasone, and olanzapine may be offered to adults treated with high-dose chemotherapy and stem-cell or bone marrow transplantation. 
• Adult patients treated with multiday antineoplastic agents should be offered antiemetics before treatment that are appropriate for the emetic risk of the antineoplastic agent given on each day of the antineoplastic treatment and for 2 days after completion of the antineoplastic regimen.
• Adult patients treated with 4- or 5-day cisplatin regimens should be offered a three-drug combination of an NK1 RA, a 5-HT3 RA, and dexamethasone.   

Breakthrough treatment

NCCN guidelines advise that the general principle of breakthrough treatment is to add one agent from a different class than in the patient's current regimen. Any of the following may be selected[2] :

• Olanzapine
• Lorazepam
• Cannabinoid (eg, dronabinol, nabilone)
• Haloperidol
• Metoclopramide
• Scopolamine transdermal
• Phenothiazine (eg, promethazine, prochlorperazine)
• 5-HT3 RA
• DEX

ASCO guidelines recommend that if breakthrough nausea or vomiting occurs, the clinician should re-evaluate emetic risk, disease status, concurrent illnesses, and medications, to ascertain that the best regimen is being administered for the emetic risk. For adults who experience nausea or vomiting despite optimal prophylaxis, ASCO recommendations are as follows:

• In patients who did not receive olanzapine prophylactically, offer olanzapine in addition to continuing the standard antiemetic regimen.
• In patients who have already received olanzapine, offer a drug of a different class (eg, an NK1 RA, lorazepam or alprazolam, a dopamine receptor antagonist, dronabinol, or nabilone) in addition to continuing the standard antiemetic regimen.   

Anticipatory nausea and vomiting

ASCO recommends that all patients receive the most active antiemetic regimen that is appropriate for the antineoplastic agents being administered, starting with the initial antineoplastic treatment, rather than assessing the patient’s emetic response with less effective antiemetic treatment. If a patient experiences anticipatory emesis, clinicians may offer behavioral therapy with systematic desensitization.[4]

Oncology Nursing Society Recommendations

The ONS practice recommendations for CINV in adults include the following[5] :

• Cannabis/cannabinoids
• Dexamethasone-sparing regimen
• Netupitant-palonosetron combination (NEPA)
• NK1 RA
• Olanzapine
• 5-HT3 RA
• Sustained-release granisetron
• Transdermal granisetron
• Triple drug regimen: NK1 RA + 5-HT3 RA + DEX

In addition, the following treatments were considered by ONS likely to be effective:

• Adherence to CINV guidelines
• Benzodiazepine for anticipatory CINV
• Gabapentin
• Hypnosis for anticipatory CINV
• Managing patient expectations
• Olanzapine for breakthrough CINV
• Oral palonosetron
• Progestins
• Progressive muscle relaxation and guided imagery
• Single-agent dexamethasone

The ONS considered the benefits balanced with harm for virtual reality, which has been evaluated for providing distraction and reducing anxiety as means of CINV prevention.

The effectiveness of the following treatments was not considered established:

• Acupressure
• Acupuncture/electroacupuncture
• Acustimulation
• Aromatherapy
• Lorazepam [Ativan], diphenhydramine [Benadryl], and haloperidol [Haldol] gel (ABH gel)
• Ayurvedic drugs
• Carbamazepine
• Chamomilla recutita
• Electronic antinausea device (ELANI)
• Exercise
• Ginger
• Grape Juice
• Guided imagery/imagery alone
• Haloperidol
• Herbal medicine
• Hologram bracelet
• Institutional initiatives
• Massage/aromatherapy massage
• Metoclopramide (prophylactic)
• Metopimazine
• Mirtazapine
• Nevasic audio
• Ondansetron as rescue medication
• Prochlorperazine for breakthrough CINV
• Progressive muscle relaxation (PMR)
• Psychoeducation/psychoeducational interventions
• Thalidomide
• Therapeutic touch
• Yoga

The ONS also found cocculine unlikely to be effective and that expert opinion supports the adjunctive use of lorazepam for CINV prevention. it is essential for the medical team to review supplemental treatments such as grape juice and others especially in combination with targeted treatments since this can alter the absorption and efficacy of these medications.

The ASCO and MASCC/ESMO guidelines categorize radiation therapy sites in terms of their risk for radiation-induced nausea and vomiting (RINV) as follows[3, 4] :

• High risk: Total body irradiation and total nodal irradiation
• Moderate risk: Upper abdomen, half body irradiation, upper body irradiation
• Low risk: Cranium, craniospinal, head and neck, lower thorax region, pelvis
• Minimal risk: Extremities, breast

Multinational Association for Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) recommendations for patients receiving radiation therapy (RT) are keyed to risk level, and include the following[3] :

• High-risk RT: : 5-HT3 RA + DEX
• Moderate-risk RT: 5-HT3 RA; short course of DEX is optional
• Low-risk RT to cranium: DEX as either prophylaxis or rescue
• Low-risk RT to head and neck, thorax region, pelvis: DEX, DOP, or 5-HT3 RA as either prophylaxis or rescue
• Minimal-risk RT: Rescue with DEX, DOP, or 5-HT3 RA

National Comprehensive Cancer Network and American Society of Clinical Oncology Recommendations

For patients receiving RT to the upper abdomen/localized sites or total body irradiation, the NCCN recommends pretreatment for each day of RT with either of the following:

• Granisetron with or without dexamethasone
• Ondansetron with or without dexamethasone

ASCO recommendations for patients receiving RT are as follows:

• High emetic risk RT - Offer a 5-HT3 RA and dexamethasone before each fraction and on the day after each fraction if RT is not planned for that day.
• Moderate emetic risk RT - Offer a 5-HT3 RA before each fraction, with or without dexamethasone before the first five fractions. 
• Low-emetic-risk RT - For adults being treated with RT to the brain, offer rescue dexamethasone therapy. For those treated with RT to the head and neck, thorax, or pelvis, offer rescue therapy with a 5-HT3 RA, dexamethasone, or a dopamine receptor antagonist. 
• Minimal emetic risk RT - Offer rescue therapy with a 5-HT3 RA, dexamethasone, or a dopamine receptor antagonist.

For breakthrough emesis, the NCCN recommendations are the same as for CINV breakthrough treatment. For management of emesis during concurrent radiation and chemotherapy, the NCCN and ASCO guidelines agree that the optimal approach is to give antiemetic prophylaxis according to the emetogenicity of the chemotherapy, unless the risk level of the radiation therapy is higher.[2, 4]

ASCO recommendations for antiemetic therapy in pediatric cancer patients are as follows[4] :

• High emetic risk antineoplastic agents - A 5-HT3 receptor antagonist, dexamethasone, and aprepitant. Patients unable to take aprepitant should be offered a 5-HT3 receptor antagonist and dexamethasone; those unable to take dexamethasone should be offered palonosetron and aprepitant.

• Moderate emetic risk antineoplastic agents - A 5-HT3 receptor antagonist and dexamethasone. Patients unable to take dexamethasone should be offered a 5-HT3 receptor antagonist and aprepitant.

• Low emetic risk antineoplastic agents - Ondansetron or granisetron

• Minimal emetic risk antineoplastic agents - Do not offer routine antiemetic prophylaxis.