The Prevention and Treatment of Nausea and Vomiting During Tumor Therapy

Background: Nausea and vomiting are common and distressing side effects of tumor therapy. Despite prophylaxis, 40–50% of patients suffer from nausea, and 20–30% from vomiting. Antiemetic prophylaxis and treatment are therefore of great importance for improving patients’ quality of life and preventing sequelae such as tumor cachexia.

Methods: The recommendations presented here are based on international and national guidelines, updated with publications retrieved by a selective search in the PubMed and Cochrane Library databases, with special attention to randomized controlled trials and meta-analyses that have appeared in the past 5 years since the German clinical practice guideline on supportive therapy was published.

Results: Risk-adjusted prevention and treatment is based on the identification of treatment-related and patient-specific risk factors, including female sex and younger age. Parenteral tumor therapy is divided into four risk classes (minimal, low, moderate, high), and oral tumor therapy into two (minimal/low, moderate/high). In radiotherapy, the radiation field is of decisive importance. The antiemetic drugs most commonly used are 5-HT3-RA, NK1-RA, and dexamethasone; olanzapine has proven beneficial as an add-on or rescue drug. The use of steroids in patients being treated with drug combinations including checkpoint inhibitors is discussed controversially because of the potentially reduced therapeutic response. Benzodiazepines, dimenhydrinate, and cannabinoids can be used as backup antiemetics. Acupuncture/acupressure, ginger, and progressive muscle relaxation are possible alternative methods.

Conclusion: Detailed, effective, risk profile–adapted algorithms for the prevention and treatment of nausea and vomiting are now available for patients undergoing classic chemotherapy regimens or combined radiotherapy and chemotherapy. Optimal symptom control for patients undergoing oral tumor therapy over multiple days in the outpatient setting remains a challenge.

Nausea and vomiting (emesis) are symptoms that considerably impair the quality of life of those affected (1). Despite prophylaxis, vomiting occurs in about 20% to 30% and nausea in 40% to 50% of patients receiving systemic therapy for cancer (2). These unwanted effects of therapy introduce further risks, as they exacerbate loss of appetite and weight loss, thus increasing the risk of cancer cachexia, with far-reaching consequences. Although in recent years sophisticated recommendations have become established for the prevention and treatment of nausea and vomiting in patients receiving classical chemotherapeutic agents, the rapid development of new antineoplastic drugs, especially oral multiday regimens, poses new challenges for antiemetic prophylaxis. Which cancer drugs even require antiemetic prophylaxis? Which antiemetics are recommended? For how long should they be given?

This article summarizes both the basic principles and recommendations for classical chemotherapy and radiotherapy, and also the risk stratification and recommendations for antiemetic prophylaxis and therapy for use with the “modern” cancer chemotherapeutics.

Learning objectives

After reading this article, readers should:

• Know the important differential diagnoses for nausea and vomiting in cancer patients;
• Be able to make a reasoned plan for antiemetic prophylaxis;
• Be familiar with effective antiemetic drugs for prophylaxis, therapy, and rescue therapy.

Method

International and national guidelines were included in the preparation of this article. In a selective update literature search in PubMed and the Cochrane Library, randomized controlled trials and meta-analyses were searched for that had been published in the last 5 years since the publication of the S3 Guideline “Supportive Therapy for Cancer Patients” (3, 4).

Definition

Loss of appetite and nausea and vomiting during treatment for cancer form an interrelated symptom complex. The classical definition is based on the timing of symptom onset: acute symptoms are those that occur on the day of treatment, while delayed symptoms are those that occur up to 5 days after treatment.

• Acute vomiting/nausea: Occurs within the first 24 hours after chemotherapy or radiotherapy. Pathophysiologically, nausea and vomiting during this time frame are mainly triggered by the release of serotonin from enterochromaffin cells of the small intestine.
• Delayed vomiting/nausea: Occurs from 24 hours to 5 days after cancer treatment. A leading part is played by the transmitter substance P, which is mainly found in the area postrema.
• Anticipatory vomiting/nausea: “Learned” symptoms resulting from a classical conditioning process resulting from the negative experience of vomiting and nausea during a previous course of chemotherapy or radiotherapy.

The limitations of this theoretical construct become clear in the face of the persistent overlapping of “acute” and “delayed” symptoms experienced by patients on multiday therapy regimens.

Use of terms

The distinctions between the terms “breakthrough therapy,” “rescue therapy,” and “secondary prophylaxis” as used in the literature are blurred. In this article, we use the term “rescue therapy” both for repeat administration of antiemetic drugs because symptoms occurred despite previous prophylactic antiemetic therapy, and for the case when, for example, antiemetic prophylaxis was previously not given because the risk was assessed as minimal, but antiemetics are now being administered. “Secondary prophylaxis” is used to refer to prophylaxis adjusted for the next cycle.

Differential diagnosis

Nausea and vomiting in cancer patients can have a number of causes and are often a sign of comorbidities or complications. If a temporal relationship with the cancer treatment is observed, it is worth reviewing the chosen antiemetic prophylaxis and ascertaining whether the patient has taken the medication. If it is not clear whether there is a temporal relationship, or if new symptoms suddenly occur during prolonged treatment, or if rescue therapy is ineffective, the many possible differential diagnoses must be carefully considered (eFigure, eTable 1).

Table 1

Emetogenic potential of radiotherapy

eFigure

Differential diagnoses in patients with nausea and vomiting

Risk factors

The risk of nausea and vomiting during cancer treatment is mainly determined by the type and intensity of the treatment, but individual patient-related risk factors also play a part.

Chemotherapy-related risk factors

The risk of nausea and vomiting during cancer chemotherapy (“chemotherapy-induced nausea and vomiting,” CINV) mainly depends on the emetogenic potential of the therapy given. Intravenous administration, high dosage, higher speed of administration, or dose-dense therapy regimens can also increase the risk of CINV, but these are not taken into account in the emetogenic risk classification.

For intravenously administered single agents, emetogenic risk is divided into 4 categories (eTable, Figure 1), ranging from minimal emetogenic risk (vomiting without prophylaxis <10%) to high emetogenic risk, where the risk of vomiting without prophylaxis is greater than 90% (5, 6). The risk profile of the active substance of the agent determines what prophylaxis is recommended.

Figure 1

Treatment algorithm for patients undergoing parenteral chemotherapy for cancer

Since 2020, the guideline panels of the American Society for Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) have limited their classification of oral chemotherapeutics to 2 risk classes: high/moderate and minimal/low (eTable 2, Figure 2) (5, 7). This simplification makes sense, given the frequent absence of information about nausea/emesis, failure to differentiate between levels of severity, and lack of clarity about antiemetic prophylaxis in the study data from phase III studies (5, 8).

Figure 2

Treatment algorithm for patients receiving oral chemotherapy for cancer

Table 2

Antiemetic agents

In the case of combination therapy, the agent with the highest emetogenic potential determines the choice of antiemetic prophylaxis. Combining two substances with the same emetogenic potential does not potentiate the risk of vomiting (an exception is anthracycline/cyclophosphamide-based chemotherapy for breast cancer, which is assessed as highly emetogenic).

Radiotherapy-related risk factors

The frequency and severity of radiotherapy-induced nausea and vomiting (RINV) mainly depend on tumor location, radiotherapy volume, individual and total dose, dose fractionation, and radiotherapy technique.

The guideline recommendations of the Multinational Association of Supportive Care in Cancer (MASCC)/ European Society for Medical Oncology (ESMO) and ASCO assess the radiation field as the most important treatment-related risk factor and distinguish 4 risk groups (5, 9) (Table 1, Figure 3). No other risk factors are currently included in the prophylaxis recommendations.

Figure 3

Treatment algorithm for patients undergoing radiotherapy

Patient-related risk factors

To date, individual patient-related risk factors have largely been identified retrospectively from studies. Patients who have suffered from other forms of nausea or vomiting during the period preceding cancer treatment, such as motion sickness or pregnancy-related nausea and vomiting, are at increased risk of nausea and vomiting during cancer treatment. An increased risk has also been described for female sex, younger age, a tendency to anxiety, and poorer health (2, 10).

In patients undergoing radiotherapy, additional patient-related risk factors reported are concurrent or recent chemotherapy, advanced cancer stage, and nausea and/or vomiting during previous treatment (11). So far, patient-related risk factors have only a subordinate role in the prophylactic treatment algorithm (Figures 1–3).

Prevention of nausea and vomiting

During the preparation for cancer treatment, antiemetic prophylaxis should receive attention and must be planned. Its efficacy must be assessed before the start of each new cycle so that it can be optimally adjusted. In the case of combination therapy, the agent with the highest emetogenic potential determines the risk class (Figure 1, eTable 2) (12).

Anticancer agents/ chemotherapy

Intravenous highly emetogenic chemotherapy (recommendations relate to one-day therapy unless otherwise stated)

Drugs such as cisplatin, carmustine, dacarbazine, or melphalan must be expected to have a high emetogenic potential. The combination of anthracyclines and cyclophosphamide in women with breast cancer is also considered highly emetogenic. Prophylaxis consisting of 5-HT₃ receptor antagonists (5-HT₃-RA), NK₁ receptor antagonists (NK₁-RA), and dexamethasone can prevent the occurrence of acute vomiting in 70% to 80% of patients. In the phase III study, the percentage of patients with complete response was significantly higher in the NK₁-RA group (72.7% [n = 260]) compared with 52.3% [n = 260] in the standard therapy group (P < 0.001) (13). Further improvement – although with sedative effects – is achieved by the addition of olanzapine. The study by Navari et al. (2016) compared olanzapine (n = 192) with placebo (n = 188). With olanzapine the rate of complete response was significantly increased in the acute, delayed, and overall periods: respectively 86% versus 65% (P < 0.001), 67% versus 52% (P = 0.007), and 64% versus 41% (P < 0.001) (14). To avoid delayed-onset vomiting and nausea, dexamethasone and, if appropriate, olanzapine should also be given on days 2–4 and aprepitant, if chosen as an NK₁-RA, on days 2–3 after cancer chemotherapy. In contrast, the addition of 5-HT₃-RA in the delayed phase does not bring any improvement.

Intravenous moderately emetogenic chemotherapy

Examples of agents with moderate emetogenic risk are anthracyclines, cyclophosphamide, and the platinum derivatives oxaliplatin and carboplatin.

For moderately emetogenic chemotherapy, the recommended prophylaxis is a two-drug combination of 5-HT₃-RA and dexamethasone. Continuing antiemetic prophylaxis on the days after chemotherapy to prevent delayed symptoms is only useful in the case of agents with known potential for delayed nausea and vomiting. Thus, for oxaliplatin, doxorubicin, or cyclophosphamide therapy, dexamethasone may be given on days 2 and 3 after chemotherapy.

In the recommendations of the S3 guideline “Supportive Therapy” and the guidelines of MASCC/ESMO and ASCO, carboplatin (AUC ≥= 4) has a special place among the moderately emetogenic substances, with an emetogenic risk higher than 80%. In this case, the addition of an NK₁-RA to a 5-HT₃-RA and dexamethasone is recommended to prevent acute nausea and vomiting on day 1; prophylaxis against delayed symptoms on subsequent days is not required.

Parenteral low or minimally emetogenic chemotherapy

For therapies with low emetogenic potential, prophylactic administration of 5-HT₃-RA, metoclopramide, or dexamethasone may be given on the day of therapy. Where the risk of nausea and vomiting is minimal, routine prophylaxis is not required. Should symptoms occur, rescue therapy is of course indicated and prophylaxis required from the next cycle onwards.

Checkpoint inhibitors are classified as low or minimally emetogenic. If antiemesis is required, 5-HT₃-RA or metoclopramide are preferred.

Parenteral highly emetogenic multiday chemotherapy

Most available study data are for the 5-day PEB (cisplatin, etoposide, bleomycin) regimen (15). The triple combination of 5-HT₃-RA with an NK₁-RA and dexamethasone was superior to the two-drug combination and is therefore a clear recommendation.

High-dose chemotherapy

A triple combination of 5-HT₃-RA with an NK₁-RA and dexamethasone is also recommended for high-dose chemotherapy (4, 16). Olanzapine can be added where high-dose chemotherapy with autologous stem cell support is given, but patients receiving allogeneic stem cell transplantation do not seem to benefit from the addition of olanzapine (5, 17).

Continuous oral chemotherapy

Once again, the emetogenic potential of oral chemotherapy is the determining factor. These drugs are usually administered over a long period, which creates a challenge: in most cases, continuous concomitant antiemetic therapy over such a long time becomes a questionable proposition, so therapy is on an individual basis. To date, randomized studies in this area have been lacking, and recommendations are therefore mostly based on expert consensus (Figure 2, eTable 2).

Oral highly/moderately emetogenic chemotherapy

Typical representatives of this group are bosutinib, temozolomide, and orally administered cyclophosphamide. For antiemetic prophylaxis, a combination of 5-HT₃-RA (days 1–7) and dexamethasone (days 1–3) is recommended. If nausea and vomiting occur after cessation of prophylaxis is attempted from day 8 of therapy, prophylaxis can be recommenced.

Procarbazine, an oral cancer chemotherapeutic agent with a very high emetogenic risk, is an exception. In this case, a triple combination of 5-HT₃-RA with an NK₁-RA and dexamethasone is worthwhile.

Oral low/minimally emetogenic chemotherapy

Agents carrying a low or minimal emetogenic risk include all the checkpoint inhibitors. In this risk category, antiemetic prophylaxis is only necessary in patients with a particular tendency to nausea and vomiting – the presence of a single risk factor, such as female sex, is generally insufficient (see above, “Patient-related risk factors”). Just as with parenteral chemotherapy, if symptoms occur, rescue therapy is necessary and prophylaxis is required from the next cycle onwards.

Radiotherapy

Recommendations for antiemetic prophylaxis during radiotherapy are organized around the 4 risk groups listed in Table 1; see also Figure 3.

High risk – total body irradiation

For patients undergoing radiation that carries a high risk of nausea and vomiting, dual prophylaxis with 5-HT₃-RA and dexamethasone is recommended, starting on the day of therapy before the irradiation and until 1 day after. To date, no randomized trials of the administration of an NK₁-RA have been carried out. The exception is simultaneous chemoradiotherapy with cisplatin, where the evidence clearly supports the addition of an NK₁-RA to 5-HT₃-RA and dexamethasone (9, 18).

Moderate risk – upper abdomen, thoracic spine/lumbar spine, neuraxis

For radiotherapy carrying a moderate risk of nausea and vomiting, 5-HT₃ RA should be given before each radiation fraction on days 1–5. In addition, dexamethasone may be given from day 1 to day 5 (19).

Low risk – pelvis, cranium, head/neck, thorax

Patients at low risk of RINV only receive antiemetics if they have symptoms. If nausea and vomiting occur during cranial irradiation, the administration of dexamethasone is recommended. If symptoms occur during irradiation of the head/neck, thorax, or pelvic region, a 5-HT₃-RA, dexamethasone, or a dopamine receptor antagonist (DRA) may be offered.

Minimal risk – extremities, breast

Antiemetic prophylaxis is also not provided for radiation treatments that entail minimal risk of nausea and vomiting. Should nausea occur, dexamethasone, a DRA, or a 5-HT₃-RA are available.

Rescue therapy during radiotherapy

For rescue therapy during radiotherapy, the drugs not yet used for prophylaxis are available. The initial preference is a 5-HT₃-RA. Although olanzapine is firmly established as a rescue antiemetic for CINV, it has not yet been investigated for this role in RINV (9). However, it is expected, by analogy, to be effective.

Combined chemoradiotherapy

Where chemotherapy and radiotherapy are combined, the risk classification is based on either the risk of the chemotherapy or that of the radiotherapy, whichever is higher. If concurrent chemoradiotherapy with cisplatin is given, there is clear evidence for the addition of a NK₁-RA to 5-HT₃-RA and dexamethasone (9, 18).

Anticipatory vomiting

Anticipatory vomiting develops from the experience of nausea and vomiting during treatment, especially in patients with individual risk factors such as a tendency to nausea or fear of treatment.

For this reason, the most effective way to prevent anticipatory vomiting is to prevent nausea and vomiting during treatment – firstly by providing effective antiemetic prophylaxis from day 1 of treatment, but also by explaining the supportive strategy, including planned antiemesis, when explaining the treatment to the patient (20). If anticipatory vomiting occurs, there is only a limited extent to which it is treatable with drugs, e.g., benzodiazepines. Behavioral therapy strategies such as desensitization, hypnosis, or progressive muscle relaxation are recommended (21).

Antiemetic agents

The following antiemetics are available (Table 2):

5-HT₃ receptor antagonists (5-HT₃-RAs) are highly effective in preventing acute nausea and vomiting during cancer treatment. Direct comparative studies between 5-HT₃-RAs showed them to be largely equieffective, although palonosetron showed efficacy in the delayed phase. Saito et al. (2009) demonstrated a complete response in the delayed phase in 315 of 555 patients (56.8%) in the palonosetron group, compared with 249 of 559 patients (44.5%) in the granisetron group (P < 0.0001) (22). Unwanted effects include headache (10% to 20%) and constipation (10% to 20%), and there may be asymptomatic and transient ECG changes with prolongation of the PR interval and QTc time and widening of the QRS complex. These ECG changes have so far not been described for palonosetron.

NK₁ receptor antagonists (NK₁-RAs) are particularly effective in the prophylaxis of delayed nausea and vomiting. More frequent side effects are fatigue (17%), belching (14%), and hiccups (4.5%). The NK₁-RAs available in Germany are moderate inhibitors of CYP3A4, so the dexamethasone dose must be reduced in a patient receiving highly emetogenic therapy (Table 2 shows the reduced dexamethasone dose). So far, no interactions with cytostatic drugs such as cyclophosphamide, docetaxel, vincristine, or etoposide have been confirmed (23, 24).

Corticosteroids – usually dexamethasone – are an essential component of antiemetic prophylaxis, although the mechanism of action is not yet fully understood. Observed unwanted effects of steroids include short-term sleep disturbances (45%), digestive problems (27%), restlessness (27%), increased appetite (19%), weight gain (16%), and acne (15%) (25).

If corticosteroids at an equipotent dose (8 mg dexamethasone corresponds to approximately 40 mg prednisone) are included in the regimen, dexamethasone for antiemesis can be omitted. For combination therapy consisting of checkpoint inhibitors and emetogenic chemotherapies, antiemetic prophylaxis with steroids is currently a matter of debate because of the possibility that it may reduce the response to cancer treatment. The ASCO guidelines (which favor steroids) and NCCN guidelines (which are against steroids) reach different assessments (5, 7). We recommend steroid prophylaxis for checkpoint inhibitors in combination with emetogenic chemotherapy. Monotherapy with checkpoint inhibitors does not require steroid administration as this entire group is now classified as minimally emetogenic. Antiemetic prophylaxis for conditioning regimens in the setting of CAR T-cell therapy should not include a steroid.

Olanzapine, an atypical antipsychotic, was initially used as a rescue antiemetic, but is now recommended for primary prophylaxis with highly emetogenic chemotherapy. The 5 mg dosage (days 1–4) should be preferred as it provides equivalent antiemetic efficacy with a better safety profile. As an atypical antipsychotic, extrapyramidal side effects are rare with olanzapine, although it has a sedative effect. Occasionally, olanzapine prolongs QTc time, which must be taken into account when it is combined with other drugs. As a rescue drug, olanzapine is the first option and clearly superior to metoclopramide. However, olanzapine is not approved for CINV.

Metoclopramide, a dopamine₂ RA, has declined considerably in importance. Because of serious unwanted effects, the maximum daily dose must be limited to 0.5 mg/kg body weight (26), and in adults the maximum dose is 10 mg three times per day. Metoclopramide can be used for primary prophylaxis with low-emetogenic-risk chemotherapy and for rescue therapy. Unwanted effects include fatigue, diarrhea, and inner restlessness. Extrapyramidal movement disorders and tardive dyskinesia occur rarely, especially in young patients.

Benzodiazepines have no primary effect as antiemetics, but their anxiolytic action and sedative effect make them effective for anticipatory vomiting. For anxious patients, a benzodiazepine may be useful as an adjunct to primary prophylaxis.

The H₁-receptor antagonist dimenhydrinate is suitable as a rescue antiemetic, but not as prophylaxis. Drowsiness is a common side effect.

Cannabinoids can be effective rescue antiemetics (27). A variety of possible side effects have been described, ranging from sedation to euphoria, hallucination, and dysphoria (28). Positive trial data have been published in a randomized phase II crossover trial on secondary prevention with oral tetrahydrocannabinol/cannabidiol (THC/CBD) cannabis extract (29). A phase III study has been initiated but its results are still awaited.

Alternative methods of prevention and treatment

Acupuncture and acupressure involve stimulating the pericardial point P6 on the wrist with an acupuncture needle or an acupressure band or thumb. A meta-analysis of randomized controlled trials showed a small effect on nausea in the acute phase (SMD = −-0.18, 95% confidence interval: [−-0.31; −-0.05], P < 0.01). The incidence of vomiting was not affected (30).

According to the S3 guideline “Complementary medicine in the treatment of cancer patients,” acupuncture or acupressure can be considered as an additional measure to reduce nausea and vomiting (31).

Study data on the antiemetic effect of ginger during the administration of cytostatic drugs are contradictory. The S3 guideline on complementary medicine lists ginger as a “may be given” option (maximum daily dose 1 g, tablet or powder) (31).

Progressive muscle relaxation is recommended to treat anticipatory vomiting (5, 8). This practiceinvolves successive tensing and relaxing of muscle groups in the body. It is regarded as a procedure with few side effects and can be learned on courses offered by health insurance companies and other organizations, or with the help of books and CDs.

Conclusion

The development of antiemetic drugs over the past 20 years has resulted in a significant lessening of nausea and vomiting during cancer chemotherapy (32, 33). Antiemetic prophylaxis during cancer therapy is not just an integral part of patient-centered care, but fundamentally necessary to the success of cancer treatment.

Acknowledgments

The authors thank Dr. Camilla Leithold for critical review and editing.

Conflict of interest statement
Dr. Jahn has received lecture fees from Tesaro and MSD. She has received reimbursement of travel expenses from Tesaro.

Dr. Brandt has received reimbursement for travel expenses from ESMO. She has received fees for being a member of the Advisory Board of Gilead.

Prof. Feyer is a member of MSD’s Advisory Board and has received study funding from MSD. She has received consultancy fees from MSD and Riemser. She has received fees for training events from MSD. She has received reimbursement of travel expenses from MSD.

Prof. Jordan has received consultancy fees from Hexal and Sandoz. She has received fees for training events from Art Tempi, Amgen, Hexal, Onkowissen, MSD, Roche, Mundipharma, Riemser, Med Update GmbH, and Vifor. She has received fees for expert opinions from AOP Orphan Pharmaceuticals Germany GmbH.

Prof. Wörmann and Dr. Freidank declare that no conflict of interest exists.

Manuscript received on 29 March 2021, revised version accepted on 16 December 2021.

Translated from the original German by Kersti Wagstaff.

Corresponding author:
Dr. med. Franziska Jahn
Universitätsklinikum Halle
Universitätsklinik und Poliklinik für Innere Medizin IV
Hämatologie/Onkologie, Ernst-Grube-Str. 40
06120 Halle, Germany

Cite this article as:
Jahn F, Wörmann B, Brandt J, Freidank A, Feyer P, Jordan K: The prevention and treatment of nausea and vomiting during tumor therapy. Dtsch Arztebl Int 2022; 119: 382–92. DOI: 10.3238/arztebl.m2022.0093

►Supplementary material

eTables, eFigure, eCaseStudy:
www.aerzteblatt-international.de/m2022.0093

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