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Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment

Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment
Petra Feyer, MD
Karin Jordan, MD
Section Editors:
Paul J Hesketh, MD
Steven E Schild, MD
Deputy Editor:
Sadhna R Vora, MD
Literature review current through: Dec 2022. | This topic last updated: Apr 05, 2022.

INTRODUCTION — Nausea and vomiting caused by radiotherapy (RT) are generally less severe than that caused by chemotherapy, but nausea and vomiting can last for a prolonged period in some cases. These side effects are clinically important and can be distressing for patients. Furthermore, RT-induced nausea and vomiting (RINV) can cause patients to delay or refuse further treatment.

The incidence, classification of risk, and management of RINV are discussed here. The approach to chemotherapy-induced nausea and vomiting is discussed separately. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

PATHOPHYSIOLOGY — The pathophysiology of RINV is incompletely understood but is thought to be similar to that caused by chemotherapy. Progress in understanding the pathophysiology of chemotherapy-induced emesis led to the development of agents that form the basis for treatment of RINV. (See "Pathophysiology and prediction of chemotherapy-induced nausea and vomiting".)

INCIDENCE — Two prospective observational studies provide information on the frequency of RINV and the extent to which this problem is treated:

The Italian Group for Antiemetic Research in Radiotherapy (IGARR) analyzed the incidence of RINV in 1020 patients receiving various kinds of RT with or without concomitant chemotherapy [1]. Overall, nausea and/or vomiting was reported by 28 percent. The median time to the first episode of vomiting was three days. Antiemetic drugs were administered to 17 percent of the patients, including 12 percent treated prophylactically and 5 percent given rescue therapy.

In another series of 368 patients receiving RT with or without concomitant chemotherapy, the overall incidence rates for nausea and vomiting were 39 and 7 percent, respectively [2]. Nausea was more frequent in those receiving RT to the lower abdomen or pelvis and to the head and neck area (66 and 48 percent, respectively). Importantly, only one-fourth of the patients reporting nausea felt that antiemetics had been beneficial, and one-third would have liked additional treatment.

The importance of RINV is illustrated by its impact on quality of life (QOL). In an analysis of patients receiving abdominal RT, a patient's subjective experiences from RINV directly correlated with the worsening of QOL outcomes [3].

RISK CLASSIFICATION — The incidence and severity of RINV depend upon details of the treatment (irradiated site and volume, single and total dose, fractionation schedule, techniques). Patient-related factors (sex, general health of the patient, age, concurrent or recent chemotherapy, psychological state, tumor stage, history of prior treatment-related nausea) are also important.

Radiation induced nausea is likely secondary to irradiation of the stomach and small intestines, causing irritation or stimulation. The most important factor appears to be the radiation field. The 2016 guidelines from the Multinational Association for Supportive Care in Cancer (MASCC) and European Society for Medical Oncology (ESMO), which have been subsequently endorsed by the American Society of Clinical Oncology (ASCO), divide the risk of emesis due to radiation therapy into four categories (table 1 and table 2) [4-6]:

High – Total body irradiation

Moderate – Upper abdominal irradiation, craniospinal

Low – Cranium (all), head and neck, thorax, pelvis

Minimal – Breast and extremities

PREVENTION AND TREATMENT — There are only limited data from randomized trials that have evaluated the efficacy of various antiemetic drugs in preventing RINV (table 3 and table 4). Generally, these trials were conducted in patients at moderate or high risk for RINV.

The available evidence from these trials indicates that 5-hydroxytryptamine (5-HT3) receptor antagonists are the most active agents that have been evaluated in randomized trials. However, other agents also have a role in some settings, especially in patients receiving concomitant chemoradiotherapy. (See "Characteristics of antiemetic drugs".)

5-HT3 receptor antagonists — The results with 5-HT3 receptor antagonists were analyzed in a meta-analysis that included nine trials [7]. In this meta-analysis, fewer patients had residual emesis compared with placebo (40 versus 57 percent, relative risk [RR] 0.7, 95% CI 0.57-0.86), and fewer required rescue medication (6.5 versus 36 percent, RR 0.18, 95% CI 0.05-0.60). Despite antiemetic prophylaxis, most patients did develop RT-induced nausea (70 versus 83 percent with placebo, RR 0.84, 95% CI 0.73-0.96).

The underlying incidence of nausea and vomiting in these trials is heavily influenced by the study populations (table 3). Taken together, these trials show that 5-HT3 receptor antagonists have significantly greater protective effect against RINV for patients receiving upper abdomen irradiation than metoclopramide, phenothiazines, or placebo [8-13]. Similarly, 5-HT3 receptor antagonists provided significantly better protection against RINV caused by total body irradiation or hemibody irradiation than conventional antiemetics or placebo (table 4) [14-18]. Separate analyses of trials comparing 5-HT3 receptor antagonists with metoclopramide also demonstrated a statistically significant benefit for the control of vomiting.

The adverse effects of 5-HT3 receptor antagonists are generally mild, consisting mainly of headache, constipation, diarrhea, and asthenia [13,14,16,19,20]. In some patients, 5-HT3 receptor antagonists reduced the frequency of diarrhea, a troublesome side effect due to acute radiation enterotoxicity [10,21].

Randomized trials in RINV have utilized five different 5-HT3 receptor antagonists (palonosetron, ondansetron, granisetron, dolasetron, tropisetron). These agents have not been compared with each other, and there are inadequate data to define optimal doses and schedules [7]. Except for very small trials, the data with palonosetron are limited to a chemoradiotherapy trial in which palonosetron was administered weekly before cisplatin [22,23].

The injected formulation of dolasetron is contraindicated for prophylaxis of RINV due to the risk of QTc prolongation from increased drug exposure [24]. Although the risk of developing an abnormal heart rhythm with oral dolasetron is less than that seen with the injection form, precautions are indicated to avoid arrhythmias, even with the oral formulation. (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Dolasetron'.)

Corticosteroids — Corticosteroids are an attractive option because of their widespread availability, low cost, and activity as antiemetics.

One randomized trial showed that dexamethasone was significantly more effective than placebo in patients receiving RT to the upper abdomen [25]. A separate randomized trial demonstrated that steroids also can prevent flair of pain when irradiating bone metastases [26], in addition to helping with nausea. Corticosteroids are often used in patients with brain metastases for management of vasogenic edema, and are also useful in managing RINV. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors", section on 'Initiation of glucocorticoids'.)

Combining corticosteroids with 5-HT3 receptor antagonists was assessed in a trial in which a five-day course of dexamethasone plus ondansetron was compared with ondansetron plus placebo in 211 patients who received RT to the upper abdomen [27]. During the first five days, there was a statistically nonsignificant trend toward complete control of nausea (50 versus 38 percent with placebo) and vomiting (78 versus 71 percent), which was the primary objective of the trial. The effects of dexamethasone extended beyond the initial five-day period, and significantly more patients had complete control of emesis over the entire course of radiotherapy (23 versus 12 percent with placebo), a secondary objective of the trial. Although this study did not demonstrate a statistically significant benefit for the primary endpoint, the results strongly suggest that the addition of dexamethasone was beneficial.

Since emesis is more frequent early in treatment, prophylactic antiemetics may not be necessary for a full course of RT, and treatment for the first week may be sufficient [25,28,29].

Neurokinin-1 receptor antagonists — Neurokinin-1 (NK-1) receptor antagonists have an established role in the management of chemotherapy-induced nausea and vomiting (CINV). (See "Prevention of chemotherapy-induced nausea and vomiting in adults", section on 'Neurokinin-1 receptor antagonists'.)

None of the NK-1 receptor antagonists have been adequately evaluated in patients at risk for RINV when RT is given without concomitant chemotherapy. However, these agents have been evaluated for patients receiving concomitant chemoradiotherapy. [30].

An observational study in patients receiving concomitant chemoradiotherapy compared the combination of aprepitant, a 5-HT3 receptor antagonist, and dexamethasone versus a 5-HT3 receptor antagonist and dexamethasone alone [31]. The three-drug combination showed a clinically meaningful benefit compared with the 5-HT3 receptor antagonist and dexamethasone alone.

In a double-blind trial (GAND-emesis study), patients with cervical cancer were treated with fractionated RT plus weekly cisplatin, using palonosetron and dexamethasone, with or without fosaprepitant, to prevent RINV [32]. Patients receiving fosaprepitant in addition to palonosetron and dexamethasone were less likely to experience nausea and emesis compared with those receiving palonosetron and dexamethasone alone.

Other agents — Older, less-specific antiemetic drugs such as prochlorperazine, metoclopramide, and cannabinoids have shown limited efficacy in the prevention or treatment of RINV, although they may have a role in patients with milder symptoms [33].

The atypical neuroleptic olanzapine was investigated in a randomized trial of patients treated with fractionated RT and concomitant cisplatin [34]. Patients received olanzapine (10 mg) or fosaprepitant (150 mg on day 1) in combination with palonosetron and dexamethasone. The complete response rate was similar for the olanzapine regimen and the fosaprepitant regimen. In the delayed and overall periods, the olanzapine regimen was significantly better than the fosaprepitant regimen.

Duration of prophylaxis — The appropriate duration of antiemetic prophylaxis for patients receiving fractionated RT is not clear and is still under study. A systematic review that included 25 randomized and nonrandomized trials found that 5-HT3 receptor antagonists were most commonly administered for the entire duration of a course of RT [35]. The decision on whether or not to continue antiemetic prophylaxis beyond the first week should be based upon an assessment of the risk of emesis as well as relevant individual factors. For example, for those receiving total body irradiation, we typically continue antiemetic prophylactic therapy on days of RT, as well as the day after each day of RT, if radiation is not planned for that day [36]. For other types of radiation, we typically do not include antiemetic prophylactic therapy on the day following treatment days, but rather on days of radiation therapy only (table 1 and table 2).

Rescue therapy — The benefits of 5-HT3 receptor antagonists once nausea or vomiting occurs has been suggested in all studies, but there are no trials specifically in this setting [37-39]. The role of rescue medication for patients at low and minimal risk of RINV needs to be defined in further studies. The emerging role of olanzapine in breakthrough emesis in patients with CINV has not been studied in RINV yet [40]; however, it is probable that olanzapine is beneficial in this setting.

PATIENT-SPECIFIC FACTORS — The risk of nausea and vomiting for a patient being treated with RT depends upon multiple other factors in addition to the emetogenicity of the specific RT regimen (ie, higher daily doses of radiation to the intestines increases nausea). Patient-specific factors include the simultaneous administration of chemotherapy, age, sex, alcohol consumption, anxiety, and previous experience of nausea and vomiting [29,41,42].

The risk categories based upon the RT regimen can be modified to incorporate these patient-specific factors. Although not prospectively proven, an approach taking these risk factors into account might further improve emesis prophylaxis in patients receiving RT (figure 1).

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The COVID-19 pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These and other recommendations for cancer care during active phases of the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)

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Basics topics (see "Patient education: Nausea and vomiting with cancer treatment (The Basics)")

SUMMARY AND RECOMMENDATIONS — Radiotherapy (RT)-induced nausea and vomiting (RINV) is a frequent complication of RT. Its incidence and severity are influenced by the specific RT regimen, region treated, and patient-specific factors (table 1 and table 2). Patients should receive antiemetic prophylaxis based upon an individualized assessment of risk, taking into account both the planned RT regimen and patient-specific factors. (See 'Risk classification' above and 'Patient-specific factors' above.)

For patients at high risk of developing RINV (table 1 and table 2), we recommend prophylaxis with a 5-hydroxytryptamine (5-HT3) receptor antagonist (Grade 1B). Based upon results from patients receiving highly emetogenic chemotherapy, we suggest the addition of dexamethasone to the 5-HT3 receptor antagonist (Grade 2B). There are no comparative clinical trials data on the use of neurokinin-1 (NK1) receptor antagonists in preventing RINV. However, in patients receiving concomitant chemoradiotherapy with cisplatin, the addition of an NK-1 receptor antagonist proved to be beneficial and should be the standard of care. (See 'Risk classification' above and "Prevention of chemotherapy-induced nausea and vomiting in adults".)

For patients at moderate risk of developing RINV (table 1 and table 2), we recommend prophylaxis with a 5-HT3 receptor antagonist (Grade 1B). In this risk group, we suggest the addition of a short course of dexamethasone to the 5-HT3 receptor antagonist during fractions 1 to 5 (Grade 2C). (See 'Risk classification' above.)

For patients at low or minimal risk of developing RINV (table 1 and table 2), we suggest not treating prophylactically (Grade 2B). If patients develop RINV, options include a 5-HT3 receptor antagonist, dexamethasone, or dopamine receptor antagonist. For patients treated with RT to the brain with RINV, we suggest dexamethasone (Grade 2C). (See 'Risk classification' above and 'Patient-specific factors' above.)

For patients being treated with concomitant RT and chemotherapy, antiemetic prophylaxis should be based upon the higher chemotherapy or RT risk category. (See 'Patient-specific factors' above and "Prevention of chemotherapy-induced nausea and vomiting in adults".)

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