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Pharm D BCOP
Clinical Pharmacy Specialist
MD Anderson Cancer Center
The available agents for the treatment of emesis are effective, but nausea and vomiting is still recognised as one of the most distressing consequences of chemotherapy. Emetogenicity varies with each chemotherapy agent and combination, but the majority of patients still experience some degree of nausea and/or vomiting. Three terms are generally used to describe the process – nausea, vomiting and retching.
Severe physiological consequences can result after prolonged symptomatic episodes. For example, malnutrition, which is especially common in the elderly, can lead to weight loss, fatigue, dehydration and electrolyte imbalances. Deficiencies in potassium, magnesium, sodium and chloride are particularly concerning due to the potential for arrhythmias, seizures and confusion when these electrolytes are low. Malnutrition resulting from nausea and vomiting can negatively impact well-being and quality of life, which may then discourage patients from pursuing further treatment for their disease.
Three phases of CINV
Chemotherapy-induced nausea and vomiting (CINV) has been described as three distinct phases. Acute CINV occurs during the first 24 hours after treatment while delayed CINV may last up to seven days following chemotherapy. Anticipatory CINV has been described as a conditional response triggered by sights, smells, tastes and thoughts, and is likely to occur in subsequent chemotherapy cycles after an episode of severe nausea/vomiting during previous treatment. Antiemetic prophylaxis should be administered with the first cycle of chemotherapy to prevent anticipatory CINV with future therapy. The American Society of Clinical Oncology (ASCO), Multinational Association of Supportive Care in Cancer (MASCC) and the National Comprehensive Cancer Network (NCCN) offer similar recommendations for the prevention of acute and delayed CINV.1–3 Different antiemetic agents are recommended according to the level of emetogenicity of the chemotherapy agent and/or combination. For the prevention of CINV with highly emetogenic chemotherapy, the NK-1 receptor antagonist aprepitant should be used in combination with a serotonin antagonist (granisetron, ondansetron, dolasetron, palonosetron) and steroid (dexamethasone). For moderately emetogenic chemotherapy, a serotonin antagonist and steroid should be used. In certain situations, the use of aprepitant may be warranted for moderately emetogenic regimens. Steroids alone serve as prophylaxis for regimens considered to be of low risk of CINV, and antiemetic agents may be unnecessary for chemotherapy known to cause minimal nausea and vomiting.
Convenient medications required
Specific recommendations for prevention and management of CINV in elderly patients undergoing chemotherapy are lacking. With the average age of the population increasing, it is likely that the number of patients over the age of 65 years with cancer-receiving chemotherapy will also continue to grow. Several concerns should be addressed with the initiation of any new medication in this patient population. Regimens for the elderly should be convenient with limited potential for adverse effects or drug interactions. Cognitive impairments with ageing, including swallowing difficulties and memory loss, necessitate the need for convenient once-daily medications when possible.
The number and type of comorbidities may impact the decision for cancer-related therapy. Cardiovascular and heart-related conditions are among the most commonly reported comorbidity in elderly patients. Diseases involving the respiratory and digestive systems, as well as diabetes and arthritis, are also common. The amount of comorbidities directly affects the number of medications required in this patient subset. Approximately 80% of elderly patients take prescription medications, with 39% of patients taking five or more.4 When designing an antiemetic regimen, avoidance of agents with numerous drug interactions, as well as limiting the potential for symptom exacerbation of comorbidities, is prudent.
Although elderly patients generally receive lower intensity therapy due to organ function or performance status, with appropriate supportive care some patients will tolerate more intense therapy. Physiological changes present a challenge for chemotherapy dosing as well as supportive care medications. Absorption of drugs via passive diffusions remains unchanged, however absorption may be compromised due to increased gastric pH, delayed gastric emptying and decreased gastrointestinal motility as a result of ageing. Half-lives of some medications may be increased as a result of increased body fat and decreased total body water. There are no age-specific changes involving the liver, with hepatic metabolism via CYP3A4, glucuronidation and acetylation all well preserved. Kidney function in the elderly may not be significantly compromised in the absence of confounding factors such as hypertension and heart disease.
Minimise adverse events
All attempts should be made to minimise adverse events and drug interactions when initiating antiemetics in the elderly. For example, aprepitant has the potential to interact with some chemotherapy agents, antifungals, antidepressants and warfarin. Certain adverse effects that may be of limited concern in younger patients can be significant in the elderly. Considering serotonin antagonists have been associated with constipation, the use of scheduled laxatives may be necessary with initiation of this type of antiemetic. In patients with cardiovascular complications receiving serotonin antagonists, particular concern exists for prolongation of the QTc interval. When used for prophylactic CINV, steroids are associated with minimal adverse effects. However, in elderly patients with diabetes, additional medication and monitoring may be necessary during the few days of therapy with steroids. In addition, concern for potential GI bleed exists in those elderly patients receiving steroids while also on chronic non-steroidal anti-inflammatory drugs for arthritic pain. Antihistamines (diphenhydramine, promethazine) and benzodiazepines (lorazepam, alprazolam) commonly used for breakthrough CINV should be avoided in the elderly due to increased risk of sedation, confusion and falls.5
Limited data exists that specifically addresses prevention and management of CINV in the elderly. Patients over the age of 65 years are often excluded from clinical trials due to age, comorbidities and organ function. However, some recent publications have specifically addressed the use of the long-acting serotonin antagonist, palonosetron, in elderly patients. Pooled data of those patients 65 years of age or older was analysed from two separate randomised, phase III studies that compared a single dose of intravenous palonosetron 0.25mg with either ondansetron 32mg or dolasetron 100mg in patients receiving moderately emetogenic chemotherapy.6 Of 165 patients included in the subanalysis, 79 received palonosetron and 86 received ondansetron or dolasetron.
The investigators defined a complete response (CR) in the acute phase as no emetic episode and no use of rescue medications during the first 24 hours after chemotherapy, CR in the delayed phase as no emetic episode and no use of rescue medications from 24–120 hours after the completion of chemotherapy and overall CR as no emetic episode and no use of rescue medication during the acute and delayed phase. Palonosetron proved significantly superior to ondansetron or dolasetron at controlling nausea and vomiting in the delayed and overall phase. In the acute phase, the rates of CR were higher with palonosetron, though this did not reach statistical significance. Constipation and headache, two of the most common adverse effects reported with serotonin antagonists, were less frequent in elderly patients receiving palonosetron compared with ondansetron or dolasetron. In a separate investigation, palonosetron in combination with dexamethasone proved safe and effective in elderly patients.7 Palonosetron 0.25mg intravenous was administered on the first day of highly or moderately emetogenic chemotherapy. Dexamethasone was administered for five days. All patients included had experienced significant CINV in a previous cycle of therapy. Patients were stratified according to age less than 65 years or age 65 years or greater, and compared for efficacy of antiemetic regimen. No significant difference was observed for occurrence of nausea and vomiting based on age, indicating that palonosetron plus dexamethasone was effective in an elderly patient population that was at high risk of CINV. Due to a prolonged half-life estimated at 40 hours, palonosetron is administered as a one-time dose. With additional advantages including lack of drug interactions, no dose adjustments for organ dysfunction and favourable safety profile, palonosetron represents a convenient option for elderly patients undergoing chemotherapy. Palonosetron displayed efficacy in elderly patients undergoing moderate and highly emetogenic chemotherapy, and spared patients of potential drug interactions with aprepitant. Further evaluations may confirm the ability of palonosetron to prevent acute and delayed CINV without the use of steroids and/or aprepitant, which can result in cost savings and avoidance of drug interactions.
In the elderly, minimal data exists to guide clinicians on antiemetic therapy. Current recommendations do not specifically address this patient population. Medications that can be administered once-daily should be offered to improve compliance, especially to patients with memory loss or confusion. Comorbidities and concomitant medications must be evaluated to prevent adverse effects and drug interactions. The need for evaluations in elderly patients will continue to be evident with the growth of the global ageing population. Until elderly-specific recommendations are available, current guidelines with considerations for elderly patient concerns are our best resources for prevention and management of CINV. n
1. Kris MG et al. J Clin Oncol 2006;24:2932–47.
2. Gralla RJ et al. MASCC Antiemetic Guidelines 2010. Available online at: www.mascc.org Accessed on 24 July 2010.
3. NCCN Practice Guidelines in Oncology v.2.2010. Available online at: www.nccn.org Accessed on 24 July 2010.
4. Jorgensen T et al. Ann Pharmacother 2001;35:1004–9.
5. Fick DM et al. Arch Intern Med 2003;163:2716–24.
6. Aapro MS et al. J Support Oncol 2005;3:369–74.
7. Massa E et al. Crit Rev Oncol Hematol 2009;70:83–91.