Assessment and management of nausea and vomiting in cancer survivors

Abstract

Nausea and vomiting may occur in cancer survivors during or independent of treatment. A complete assessment is necessary to determine the etiology and to plan specific and successful interventions. NPs have a key role in managing cancer survivors' symptoms and determining the best supportive care.

In Brief

Nausea and vomiting may occur in cancer survivors during or independent of treatment. A complete assessment is necessary to determine the etiology and to plan specific and successful interventions. NPs have a key role in managing cancer survivors' symptoms and determining the best supportive care.

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According to the National Comprehensive Cancer Network (NCCN), “an individual is considered a cancer survivor from diagnosis, through the balance of life.”¹ There are essentially two types of cancer survivors: those living with cancer and those free of cancer.¹ Some patients embrace the term cancer survivor, whereas others do not identify as cancer survivors early after diagnosis or while on active treatment. By 2040, it is expected that there will be more than 26 million cancer survivors.² This increase in cancer survivors is attributed to the growth and aging of the population, earlier detection, and advances in treatment.² Cancer survivors may experience physical and psychological effects during or after cancer treatment. Nausea and vomiting (N/V) are examples of physical effects commonly experienced by cancer survivors.

N/V are reported in 40% to 55% of patients receiving chemotherapy and are some of the most feared adverse reactions of cancer treatment.³ An estimated 50% to 80% of patients receiving radiation therapy experience N/V, with those receiving total body or upper abdomen radiation at highest risk.⁴ For those patients not receiving active treatment, N/V may still occur as symptoms of the cancer or as the result of drug therapy and other causes. Both oncology and primary care NPs are critical members of the healthcare team who should be aware of the etiologies and management of N/V in cancer survivors. Unfortunately, healthcare providers often underestimate the incidence of N/V in patients with cancer, resulting in a discrepancy between perception and patients' actual experience as well as in the failure of antiemetic treatment.⁵ Prompt assessment and management of N/V in the cancer survivor can help to prevent physical and mental consequences and improve quality of life (QOL).

Definitions

Nausea is defined as a subjective feeling generally entailing a perception of being “sick to one's stomach” or queasy. This can be a prolonged unpleasant sensory and emotional experience. Nausea may be difficult to describe but often includes uncomfortable sensations in the throat, epigastric area, or abdomen. Anorexia, or loss of appetite, often accompanies nausea. It is important to assess the timing and severity of each of these symptoms. Although nausea may be considered a precursor to the act of vomiting, it does not necessarily exist on a continuum with vomiting, and N/V may not occur in combination with each other.⁶ Vomiting is the forceful expulsion of foods or liquids from the stomach through the oral or nasal cavity. The sensation of nausea and the act of vomiting may be considered protective mechanisms or reflexes that rid the gastrointestinal (GI) tract of toxic substances. Retching is an attempt to vomit without producing any foods or liquids and is also known as “dry heaving.” Although nausea, vomiting, and retching are sometimes used interchangeably, they are distinct terms and should be assessed individually.⁶ Attention to language and cultural diversity must be considered to obtain the most accurate assessment.

Chemotherapy-induced N/V (CINV) can be acute, occurring within 24 hours of chemotherapy, or delayed, occurring 25 to 120 hours later. Breakthrough CINV occurs within 5 days of chemotherapy administration despite the use of prophylactic drugs, and it often requires additional rescue medication. Refractory CINV, or N/V occurring during subsequent cancer treatment cycles after ineffective prevention and management during earlier cycles, can be a challenge.^7,8 Anticipatory CINV, defined as a conditioned response from a previous poor experience with chemotherapy, occurs before the patient's next treatment and is particularly difficult to manage; anxiety is a primary factor.⁸

Pathophysiology

The two main brainstem centers that are thought to be responsible for N/V include the vomiting center (VC) and the chemoreceptor trigger zone (CTZ).³ These centers receive and integrate input from the cerebral cortex, vestibular system, and GI tract (see Neurologic pathways involved in emesis). It is suggested that emesis may be mediated primarily through input from neurotransmitters in the GI tract and central nervous system, although these mechanisms are based on observations from animal studies and are not well defined.³

Figure: Neurologic pathways involved in emesis

Several neurotransmitter receptors located in the VC, CTZ, and GI tract may be activated by chemotherapy and radiation therapy to cause vomiting. N/V may be mediated by 5-hydroxytryptamine (serotonin), dopamine, substance P, histamine, and cannabinoids (see Proposed CINV pathways and Neurotransmitters involved in CINV). The pharmacologic approaches to control N/V in cancer have significantly improved due to the identification of implicated neurotransmitters and their receptors as well as development of agents that block these receptors.³

Figure: Proposed CINV pathways

Figure: Neurotransmitters involved in CINV

Etiologies

In cancer survivors, the most obvious causes of N/V are related to treatment. Both parenteral and oral chemotherapy can cause N/V, with specific agents, dosing, and schedule affecting incidence. Emetogenicity of chemotherapeutic agents is classified as high (>90% risk of CINV), moderate (30% to 90% risk of CINV), low (10% to 30% risk of CINV), or minimal (<10% risk of CINV).^7,9 Typically, chemotherapy regimens rather than individual agents are used for stratification of emetogenicity.

Immunotherapy is increasingly becoming an integral component of cancer therapy. It is used for numerous cancer types as monotherapy or in combination with chemotherapy. GI immune-related adverse events (irAEs) can involve the bowels, liver, and pancreas and may present as nonspecific symptoms of nausea, vomiting, and abdominal pain.¹⁰ Although uncommon in clinical practice, N/V are reported in approximately 36% of patients with upper GI toxicity from immunotherapy.¹⁰ In most cases, symptoms are mild; however, moderate or severe symptoms can cause significant morbidity, potentially leading to hospitalization and inability to continue cancer treatment. One example is irAE gastritis, which may present with nonspecific symptoms of nausea, vomiting, and loss of appetite. GI irAEs seem to develop more frequently in those receiving combination immunotherapy or combination chemotherapy and immunotherapy, due to GI mucosal injury that is a toxicity of both types of agents.^10-12

Radiation therapy can also cause N/V, especially for patients receiving total body radiation or radiation to the GI tract, liver, or brain. A larger treatment field, higher number of fractions, and higher overall dose, as well as receipt of concurrent chemotherapy and radiation therapy, increase the risk.^4,13

There are also nontreatment-related causes of N/V. Cancers of the brain, GI tract, and liver may cause N/V; additionally, N/V may be a sign of advancing disease. It has been noted that approximately 40% of patients with cancer experience nausea and/or vomiting within the last 6 weeks of life.^14,15 Potential causes of N/V include impaired gastric emptying and other causes of delayed GI transit, such as bowel obstruction, GI bleed, enteritis, and constipation.¹⁴ In addition, chemical abnormalities, such as hypercalcemia, hyponatremia, or those resulting from renal or liver failure, can cause N/V. Medications such as opioids, antibiotics, and antidepressants may contribute to N/V. Patients with viral or bacterial infections may develop fever and chills, associated with or shortly followed by N/V. Fungal infections, such as oral candidiasis, also have the potential to cause increased nausea and dysgeusia or ageusia.¹⁵ Anxiety and depression often are associated with N/V, with multifactorial etiologies and psychological components. Similarly, pain can contribute to N/V both physically and psychologically; adverse reactions of opioids used for the pain may further compound the situation.¹⁶ Anorexia and dehydration often accompany N/V, and accompanying biochemical abnormalities may contribute to N/V.¹⁴ Patients with cancer often have clusters of these symptoms, increasing the complexity of assessment and management.

Assessment

A detailed history of N/V should include their frequency, timing, and associated activities. Other signs and symptoms such as appetite and weight loss should also be assessed. Symptom assessment tools can be useful and are often available through the electronic health record (EHR). Examples of patient-reported symptom assessment tools include the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE^®), the Edmonton Symptom Assessment Scale/System (ESAS), and the Memorial Symptom Assessment Scale (MSAS).¹⁷ The Patient-Reported Outcomes Measurement Information System (PROMIS) has reliability and validity for use specifically in patients with cancer. Using the PROMIS screening tool in the clinical setting in the computer-adaptive testing (CAT) format allows for brief and reliable measurements and results that can be utilized in standard clinical practice. Score thresholds can be designated so that higher scores automatically trigger alerts in the EHR. Future developments include applications for self-management support for psychosocial concerns and physical symptoms.¹⁸ At a minimum, a visual analogue scale with a range of 0 (no nausea) to 10 (worst possible nausea) can be used. Incorporation of patient-reported outcome measures (PROMs) into routine clinical practice can improve the assessment and monitoring of the course of symptoms over time, identification of chief complaints and concerns, and decision-making and treatment planning.¹⁸

The history should also include a medication reconciliation, with prompting questions about prescription and over-the-counter medications as well as vitamins and herbal supplements. Any recent or remote treatment with chemotherapy, immunotherapy, hormone therapy, or radiation therapy should be noted. The medication history is essential to identifying medications that may contribute to or cause N/V.

A focused physical exam should assess for signs of dehydration, including evaluation of skin turgor, mucous membranes, and orthostatic vital signs.^19,20 Signs of dehydration in older adult patients may also include upper body muscle weakness, confusion, and speech difficulty.^19,20 A formal clinical dehydration scale may be used; however, there are some limitations in the physical exam component compared with lab testing.²⁰ Providers should also assess for bowel sounds; abdominal pain, tenderness, and distension; ascites; hepatomegaly; and splenomegaly. Presence of abnormal findings such as pain or tenderness may indicate internal pathologic conditions such as bowel obstruction, gastroparesis, or an inflammatory process. A neurologic exam is indicated for patients with a history of cancer, especially evaluating for signs of increased intracranial pressure or central nervous system abnormalities.¹⁹ (See Case study and Concept map of N/V in cancer survivors.)

Figure: Concept map of N/V in cancer survivors^3,7,8,17-23

Prevention of CINV

Beginning with a risk assessment of the emetogenicity of the chemotherapy and patient-specific risk factors, it is important to plan for prevention of CINV with appropriate antiemetics. Antiemetic prescription is often based on the level of emetogenicity of the chemotherapy. Both parenteral and oral chemotherapy have the potential to cause CINV.

Patient-specific risk factors should also be considered when planning the antiemetic regimen. A more rigorous approach may be needed to minimize CINV in higher-risk patients. Established risk factors include younger age (less than 60 years), female sex, history of low alcohol intake, history of pregnancy-induced emesis or motion sickness, history of vomiting in a previous chemotherapy cycle, type of chemotherapy administered, and type of antiemetic administered. Risk factors with limited evidence include anxiety, expectation of CINV, the first two cycles of chemotherapy, concomitant use of opioids, concomitant use of selective serotonin reuptake inhibitors, and less than 7 hours of sleep the night before chemotherapy.^3,21

Figure: Decision tree for antiemetic therapy^7,9,24,26

Management of CINV

Strategies to manage CINV should be multifactorial and involve several approaches for better control. The first step in the management of N/V in cancer survivors should be directed at an identified specific cause. Suspected offending medications should be evaluated for potential discontinuation or rotation to an alternative that is less likely to cause N/V.¹⁹ Correction of suspected etiologies when possible is another important initial action. Subsequent efforts are directed at neurotransmitter receptors that may be contributing to the N/V through pharmacologic therapy.

Many professional organizations have developed evidence-based consensus guidelines for the management of N/V in cancer survivors.^7,9 The management of CINV, radiation-induced N/V (RINV), and N/V experienced outside of active treatment by cancer survivors can be optimized through use of these current clinical guidelines.

When selecting pharmacologic agents for the prevention and management of CINV, patient-specific risk factors and the emetogenic risk of the planned therapy should be considered (see Decision tree for antiemetic therapy).^7,9 Commonly used agents include serotonin receptor antagonists (such as dolasetron, granisetron, and ondansetron), neurokinin-1 receptor antagonists (such as aprepitant, fosaprepitant, and rolapitant), and dexamethasone. These drugs have been effective in preventing emesis in the majority of patients; however, they are not as effective in preventing nausea.⁷ There are both short- and long-acting serotonin receptor antagonists available; these should not be combined due to risk of compounded toxicities.⁷ More recent guideline updates have included the atypical antipsychotic olanzapine (off-label for this indication) to prophylactic regimens for preventing N/V in those receiving moderately or highly emetogenic chemotherapy.^7,9 Providers should refer to NCCN, American Society of Clinical Oncology (ASCO), or other appropriate guidelines for details on combination antiemetic regimen options and dosing.

For those experiencing breakthrough N/V following prophylactic treatment, dopamine antagonists (such as phenothiazines, metoclopramide, and olanzapine) or dexamethasone may be effective. It is unlikely that an agent used as prophylaxis, such as a serotonin receptor antagonist, will be helpful for this type of N/V. Benzodiazepines such as lorazepam given before subsequent treatments may be helpful for anticipatory N/V.^7,8

Hydration in the form of I.V. fluids may be an additional supportive measure. Unscheduled I.V. fluid infusions administered in the ED or during hospitalization are associated with substantial costs. Outpatient clinic evaluation and I.V. fluid administration is preferred when indicated.²² It is also important to review the antiemetic regimen of patients requiring I.V. fluids to ensure guideline adherence. Providers must also be diligent in the documentation of subjective and objective data relating to the patient's N/V, as well as other factors such as diarrhea or orthostatic hypotension, that support the need for I.V. hydration. Use of specific, current International Classification of Diseases, Tenth Revision, Clinical Modification codes is essential for proper documentation and reimbursement.²³

To achieve better control of CINV, other factors may impact decision-making. Antiemetic availability and economic considerations may affect the selection and prescription of antiemetics. Providers who follow antiemetic guidelines such as those of the NCCN, ASCO, and Multinational Association of Supportive Care in Cancer/European Society of Medical Oncology (MASCC/ESMO) can improve patient outcomes and reduce associated costs.^7,21,24-26 In addition, these guidelines can be used as sources of evidence to submit to patients' health insurance providers for prior authorizations for antiemetic therapy. Patient adherence to the antiemetic regimen is critical for the control of CINV and should be emphasized from the outset. Nonpharmacologic approaches may also benefit patients in reducing CINV; however, the data are limited. Dietary approaches, behavioral approaches, acupuncture/acupressure, and ginger have had mixed results but may have a complementary role in minimizing CINV.⁸

Treatment of irAEs may improve N/V related to immunotherapy. For example, treatment of irAE gastritis with corticosteroids is often associated with rapid improvement. In corticosteroid-refractory cases, further evaluation with endoscopy and treatment with an antitumor necrosis factor-alpha monoclonal antibody may be indicated.¹¹ It is important to note that the decision to prescribe steroids for patients receiving immunotherapy should be made in collaboration with the patient's oncology provider.

Prevention and management of RINV

Fewer randomized clinical trials have been conducted on RINV. NCCN, ASCO, and MASCC/ESMO guidelines are categorized by level of risk according to radiation site.^7,9,24-27 All agree that dexamethasone and serotonin receptor antagonists may be effective for prophylaxis of RINV in those with the highest level of risk (individuals undergoing total body irradiation). Radiation of the upper abdomen or craniospinal area is classified as moderate emetic risk; use of a serotonin receptor antagonist and/or dexamethasone is recommended. When concurrent chemotherapy and radiation are administered, it is recommended that the antiemetic regimen be prescribed as appropriate for the chemotherapy regimen.^4,7,24-27 For breakthrough N/V related to RINV, providers should administer a drug from a different class than the agent(s) administered as prophylaxis.

Management of N/V unrelated to treatment

N/V that occurs outside of active cancer treatment may be chronic and difficult to manage. The etiology may be unclear, necessitating an empirical approach. In advanced cancer, preferred agents include dopamine receptor antagonists, titrated to maximum benefit and tolerance. If N/V continue, use of other drug classes, such as corticosteroids, serotonin receptor antagonists, antipsychotics, anticholinergics, antihistamines, cannabinoids, or antidepressants, may be considered. Patients experiencing N/V outside of active cancer treatment may be receiving hospice care or palliative measures only, with a primary goal of symptom relief. Another consideration for patients receiving hospice care or palliative measures only is selection of an appropriate route of administration. Oral, sublingual, or rectal agents should be titrated to maximum benefit. If N/V persists, changes in dosing, such as p.r.n. or scheduled dosing or a continuous parenteral infusion, may be necessary.²⁸

Palliative care services. Introduction of palliative care early in the disease course and concurrent with active treatment can have a major impact on a patient's QOL. Patients with cancer often experience more than one symptom at any given time, and interdisciplinary palliative care teams are able to assist with multiple symptoms that may be related or unrelated to the cancer. In addition, patients who experience complex or refractory symptoms may benefit from specialist palliative care services, which have been shown to improve patient outcomes.^28,29

Vulnerable populations

Pediatric patients with cancer. Symptom distress and decreased QOL have been documented in children with cancer. Older children in particular experience worse QOL. Pain and nausea are the most prevalent distressing symptoms reported by children with cancer.³⁰ The Pediatric Nausea Assessment Tool (PeNAT) is an example of a validated tool that may benefit pediatric oncology practice. Integration into the EHR may be beneficial for real-time assessment and personalized interventions.³¹ The Children's Oncology Group has endorsed evidence-based guidelines for the management of CINV in pediatric patients with cancer.³²

Older adults with cancer. The number of older adults with cancer is increasing, and many will undergo cancer treatments. With a growing number of older adults becoming cancer survivors, continued supportive care will be needed. As older adults typically have more comorbidities, risks of dehydration and renal impairment with N/V are higher.³³ Despite receiving patient education on adverse reactions, many older adults do not practice appropriate self-management. Debriefing, with review and discussion of symptom strategy outcomes, may increase knowledge of self-management strategies. Tracking or recording self-management behaviors may benefit older adults and reinforce the value and importance of their use at home.³⁴

Telehealth and innovative approaches

Many patients experiencing N/V self-manage symptoms at home. With the recent increased use of telehealth, technology-aided patient assessment is a potential strategy to help improve symptom outcomes and decrease overall healthcare costs.³⁵ With the movement toward a value-based healthcare system, these interventions have the potential to minimize unplanned clinic and ED visits as well as hospital admissions. Increased telephone conversations, self-management coaching, automated symptom monitoring, and NP follow-up utilizing guideline-based decision support in between scheduled office visits have been shown to decrease symptom burden in patients with cancer.³⁵

As a discipline, advanced practice nursing has developed expertise and leadership in symptom management. Symptom management has been a respected role of NPs, and NPs are in an excellent position to promote quality improvement, utilization of evidence-based guidelines, and timely interventions. The use of digital tools is an example of innovation, interdisciplinary collaboration, and leadership in improving symptom management and patient outcomes. Assessments and interventions that link to the EHR may create new workflows that positively impact symptom management.³⁶

Collaboration of primary care and oncology providers

Throughout the cancer survivorship continuum, N/V assessment and management often involves both primary care providers (PCPs) and oncology providers. Although a shared goal is to provide coordinated, quality care for cancer survivors, the PCP and oncology provider relationship and communication may be lacking or absent. Communication, patient care, and patient and provider satisfaction can be improved by establishing roles for each provider at various phases of care. It is recommended that the oncology provider make personal contact with the PCP after the initial referral, with significant changes in patient condition, and at discharge. Oncology providers often provide survivorship care plans to PCPs, and these plans can assist in care beyond active treatment.³⁷

Conclusion

The assessment and management of N/V in the cancer survivor is important throughout the continuum of care. Prompt, stepwise assessment and interventions directed at the cause of the N/V are critical in improving symptom control and patient QOL. NPs play a key role in leading this effort, reducing barriers, and providing patient-centered care.

Case study

Susan is a 72-year-old female with a history of stage II, estrogen receptor- and progesterone receptor-positive, HER2-positive breast cancer diagnosed 2 years ago. She underwent surgery and chemotherapy/immunotherapy for her cancer. She calls her primary care office after experiencing 3 days of N/V and dull headache. She states she thought she had “the flu” and has been able to drink liquids only. She has not taken any medication for nausea. She lives with her husband only and reports that he has not recently been ill. She is offered an office visit with her primary care NP. Upon arrival, she is noted to be afebrile with a 10-lb weight loss, pulse of 84 beats/minute, and a BP of 138/78. She endorses a continued frontal headache. She is alert and oriented. Her skin turgor is brisk. Her abdomen is nontender and nondistended with bowel sounds present in four quadrants. Lab studies, including complete blood cell count and comprehensive metabolic panel, are ordered. The primary care NP evaluates possible differential diagnoses and considers other diagnostic studies that may be indicated. In addition, a call is made to Susan's oncology NP to confer about the case.

Because of her weight loss, headache, and history of HER2-positive breast cancer, it is recommended that Susan undergo an MRI of the brain with and without contrast. The patient is prescribed ondansetron 8 mg P.O. every 8 hours as needed for nausea. The MRI is completed within 48 hours, and results are consistent with diffuse brain metastases. Her N/V improves with ondansetron. Further follow-up is planned with her medical oncologist and radiation oncologist for treatment of the metastatic cancer.