Chemotherapy-Induced Nausea and Vomiting: Which Antiemetic for Which Therapy?

ABSTRACT: Chemotherapy-induced nausea and vomiting (CINV) remains an important and common toxicity of cancer treatment. Recent guideline revisions have classified chemotherapeutic agents into four categories of emesis risk without the use of preventive agents: high (> 90%), moderate (30%-90%), low (10%-30%), and minimal (< 10%). Currently available antiemetic agents, including corticosteroids, 5-hydroxytryptamine (HT)3 receptor antagonists, and neurokinin (NK)-1 antagonists are used alone or in combination depending on the level of emetogenic potential as prophylaxis against the development of CINV during the acute period (up to 24 hours after chemotherapy) and the delayed period (up to 5 days after treatment). Newer agents, including the second-generation 5-HT3 receptor antagonist palonosetron(Drug information on palonosetron) (Aloxi) and the NK-1 antagonist aprepitant (Emend), offer additional clinical benefit in highly and moderately emetogenic therapy. However, delayed nausea and vomiting continue to occur frequently in many patients and have an impact on quality of life. Other classes of agents including the benzodiazepines and cannabinoids offer the potential for additional protective benefit. Continued research with new drugs and combinations is necessary to meet this significant unmet need of cancer patients.

Nausea and vomiting caused by the the administration of cancer chemotherapy (CINV) is one of the most common and distressing side effects of cancer treatment.[1] Arguably, the development of effective combination chemotherapy regimens capable of prolonging lives and curing patients could not proceed until the parallel development of effective CINV prevention and treatment strategies. Indeed, I vividly remember young testicular cancer patients in the early 1980s who were extremely reluctant to continue curative high-dose cisplatin(Drug information on cisplatin)-based treatments following one cycle delivered without effective antiemetic therapy. Advances in antiemetic development thankfully make such a situation extremely rare today.

This review will focus on the updated classification of the emetogenic potential of available chemotherapeutic agents and current recommendations for the prevention and treatment of CINV based on recent clinical trial evidence.

Physiology of Emesis

Central to the development of modern antiemetic therapy was the understanding of the physiology behind the emetic response. Vomiting is a natural protective mechanism against the ingestion of toxic agents and results from signals triggered by pathways in both the brain and gastrointestinal (GI) tract. A chemoreceptor trigger zone (CTZ) in the brainstem is activated by noxious stimuli and, in turn, stimulates the vomiting center in the medulla. The vomiting center sends signals for salivation, respiratory change, and pharyngeal, GI, and abdominal muscle contractions, which result in vomiting. The enterochromaffin cells of the GI tract contain receptors that can trigger the afferent vagus nerve to stimulate the CTZ and initiate the emesis process.[2]

Multiple neurotransmitters are involved in this physiologically complex process. The most important neuroreceptors are the 5-hydroxytryptamine (HT)3 or serotonin receptors, the dopamine(Drug information on dopamine) receptors, and the neurokinin (NK)-1 receptor, but others include those for histamine, endorphins, acetylcholine, cannabinoids, and gamma-amino butyric acid (GABA). Typically, multiple receptors are involved in an emesis event.[3] Antagonists to one or more of these receptors form the basis of pharmacologic emesis control.[4]

Classification of CINV

CINV can be classified into four general categories: acute, delayed, anticipatory, and breakthrough. Acute CINV is defined as nausea and/or vomiting occurring in the first 24 hours following chemotherapy administration. Delayed CINV is arbitrarily defined as occurring after the first 24 hours and up to 120 hours after chemotherapy.[5] Anticipatory CINV is a learned or conditioned response that occurs in patients who have had poorly controlled nausea and vomiting during prior chemotherapy. Anticipatory CINV has been reported in up to 18%-57% of patients[6] and typically responds better to behavioral modification or nonpharmacologic approaches.

Primary and secondary prophylaxis against each of these types of CINV reduces the risk of events. However, some patients develop breakthrough CINV, defined as episodes occurring despite appropriate prophylactic use of antiemetics. Breakthrough CINV is generally addressed through the use of antiemetic agents in classes other than those used during the prophylactic phase.

Classification of Chemotherapeutic Agents by Emetogenic Risk

A major advance in determining risk for CINV by agent was achieved in 1997, when Hesketh et al devised a classification schema dividing chemotherapeutic agents into five levels according to the percentage of patients experiencing acute emesis without prophylactic antiemetic therapy in clinical trials: level 1 (< 10%), level 2 (10%-30%), level 3 (30%-60%), level 4 (60%-90%), and level 5 (> 90%).[7] This system was updated by Grunberg and colleagues in 2005 by collapsing the levels into four categories of risk: > 90%, 30%-90%, 10%-30%, and < 10%.[8] In patients receiving combination chemotherapy, the highest-level drug defines the risk. In addition, a separate classification for oral agents was provided.

TABLE 1

Emetogenic Risk Associated With Intravenously Administered Antineoplastic Agents

In 2006, the American Society of Clinical Oncology (ASCO) published a revision of their evidence-based antiemetic guidelines—the first update of their recommendation since 1999.[9] National Comprehensive Cancer Network (NCCN) guidelines, updated yearly by consensus standards, classify agents very similarly to the ASCO guidelines.[10] The 2006 revised emetogenic risks for antineoplastic agents are presented in Table 1. Agents in the highest-risk group include many drugs no longer regularly employed in current chemotherapy regimens but do contain cisplatin and dacarbazine(Drug information on dacarbazine).

The moderate-risk group (> 30%-90% emesis risk) contains many of the commonly used drugs to treat cancer including carboplatin, oxaliplatin(Drug information on oxaliplatin) (Eloxatin), cyclophosphamide(Drug information on cyclophosphamide), doxorubicin(Drug information on doxorubicin), epirubicin(Drug information on epirubicin) (Ellence), and irinotecan (Camptosar). Drugs considered to have low emetogenic risk (10%-30%) include the taxanes, etoposide(Drug information on etoposide), and biologics such as trastuzumab(Drug information on trastuzumab) (Herceptin) and cetuximab(Drug information on cetuximab) (Erbitux). Some antineoplastic agents such as the vinca alkaloids as a class or bevacizumab(Drug information on bevacizumab) (Avastin) are associated with minimal risk of emesis without prophylaxis (< 10%). Clinicians should be aware of recent changes in the 2006 ASCO guidelines—for example, paclitaxel and gemcitabine (Gemzar) being reclassified as low-risk rather than minimal-risk drugs while others (eg, vincristine, fludarabine) have changed from low to minimal risk.

In addition to the type of chemotherapeutic agent, patient-specific risk factors are known to increase the likelihood of developing CINV. These include age < 50 years, history of light alcohol use, history of vomiting associated with previous chemotherapy, nausea or vomiting during pregnancy, history of motion sickness, and extreme anxiety.[11] Gender also plays a role, as women are more likely to experience CINV than men. A complete patient history aids in identifying historical risk factors that can affect the level of emetogenic risk and alter the antiemetic therapy prescribed.