Adherence to antiemesis guidelines is not very good, especially with highly emetogenic chemotherapy. If you do adhere to the guidelines, you have better control over nausea and vomiting, but choosing wisely is using what you need—and nothing more.— Frankie Ann Holmes, MD
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The optimal use of new antiemetics was the subject of a presentation at the 14th Annual School of Breast Oncology, Emory University, Atlanta, by Frankie Ann Holmes, MD, Associate Director of Breast Oncology Research at Texas Oncology, Houston. “The science of nausea and vomiting is so compelling, and it just keeps unfolding,” Dr. Holmes commented.
In focusing on some of the newer issues in emesis protection, Dr. Holmes described sustained-release granisetron (Sustol; approved in August 2016) and a liquid cannabinoid, dronabinol oral solution (Syndros; approved in July 2016) and shared some thoughts on emesis pathophysiology and optimal treatment.1
Extended-Release Granisetron
The new extended-release granisetron is a polymer-based drug delivery system that is administered by subcutaneous injection to patients receiving moderately emetogenic and highly emetogenic chemotherapy. In a noninferiority trial in patients receiving moderately emetogenic chemotherapy, a complete response during the acute phase (0–24 hours) was achieved by 83% of granisetron recipients, compared with 89% of those receiving intravenous palonosetron (Aloxi).2 For patients receiving highly emetogenic chemotherapy (anthracycline/cyclophosphamide), early complete responses were seen in 70% and 64% of the arms, respectively. Delayed response rates were fairly similar.
Prolonged constipation can be a problematic side effect of extended-release granisetron, but QTc syndrome is not an issue with this drug. The most serious concern, although rare, is serotonin syndrome, a potentially life-threatening condition that can occur with 5HT3 (serotonin) receptor antagonists, especially in combination with certain other medications, said Dr. Holmes. This syndrome was first described in the death of an 18-year-old college student, Libby Zion, in March 1984, caused by the combined use of meperidine and phenelzine.3 In 2016, a patient died of serotonin syndrome related to an overdose of venlafaxine and benzodiazepines.4
Serotonin syndrome is caused by an excessive amount of serotonin occupying central nervous system and peripheral nerve receptors. It can cause massive serotonin discharge, leading to mental status changes, autonomic hyperactivity, and neuromuscular abnormalities such as tremor and ocular clonus. “The serotonin syndrome is more relevant than ever with supportive care drugs,” she said. The condition has a variable course, and in severe cases, patients must be intubated and paralyzed to prevent the muscle activity that causes very high fever and subsequent rhabdomyolysis and renal failure.
Ondansetron, granisetron, and metoclopramide are on the list of drugs that can produce “severe” serotonin syndrome. Many other drugs commonly used in cancer care also may have this effect, including selective serotonin-reuptake inhibitors, antidepressants (venlafaxine), some analgesics and anticonvulsants, and even some herbs (St. John’s wort, ginseng). “There are lots of drugs on this list, and you have to be aware,” she cautioned.
New Cannabinoid Approved
An oral solution of dronabinol, is indicated for nausea and vomiting that does not respond to standard antiemetics, was recently approved. For prevention of emesis, after its preparation in a calibrated syringe (4.2 mg/ m2), dronabinol is given on an empty stomach 1 to 3 hours prior to chemotherapy (half the dose for elderly patients). This regimen is followed by dosing every 2 to 4 hours for 4 to 6 doses.
Cannabinoids bind to many receptors in the brain, and their biologic activity depends on which receptors are activated. There are three classes of cannabinoids: endocannabinoids, phytocannabinoids, and synthetic cannabinoids (of which dronabinol is one). Their efficacy in emesis has not been tested against 5HT3 receptor antagonists, “only older drugs,” but they are “likely similar” and may have a better therapeutic index as a result of less toxicity, according to Dr. Holmes.
Update on Newer Antiemetics
- Two new antiemetics were approved in 2016: sustained-release granisetron (subcutaneous) and a liquid cannabinoid, dronabinol.
- A rare but potentially fatal side effect of 5HT3 receptor antagonists is serotonin syndrome; physicians should be aware of it, especially when these drugs are given with certain other medications.
- Physicians should have zero tolerance for emesis but “choose wisely” with regard to the right agents, the right dose, and the right patients.
Cannabinoids do, however, carry some risk for adverse events. The psychotropic form, THC (delta-9-tetrahydrocannabinol), when vaporized (smoked) can be contaminated with aspergillus, “and we worry about this in transplant patients,” she said.
Other potential side effects of concern with dronabinol are hypotension and syncope. This agent should not be taken with grapefruit juice or clarithromycin, which inhibit CYP3A4 and thus affect its metabolism.
New Data on Emesis Pathophysiology
It has recently been shown that the neurokinin (NK1) receptors are widely distributed throughout the body, including the gastrointestinal tract. The implication is greater crosstalk with 5HT3 receptors, meaning that NK1 receptor blockade may be of benefit, even in the acute phase (0–24 hours), and 5HT3 receptor blockade may have benefit in the delayed phase (24–120 hours). “This tells us that combination therapy may have more effects than just those in the brain,” revealed Dr. Holmes.
Newer Options for Highly Emetogenic Chemotherapy
In the absence of prophylaxis, 90% of patients receiving highly emetogenic chemotherapy will experience emesis. Updated guidelines recommend treating patients with one drug in each of the three indicated classes. Patients receiving moderately emetogenic chemotherapy have a 30% to 90% risk for emesis; therefore, “some have to be treated as highly emetogenic chemotherapy, as some are more sensitive,” Dr. Holmes pointed out. “For minimal-risk patients, on the other hand, you need to give very little prophylaxis.”
Recipients of highly emetogenic chemotherapy should be treated with a 5HT3 receptor antagonist, dexamethasone, and an NK1 receptor antagonist and/or olanzapine (for 5 days). Other agents can be added as needed, including lorazepam and a proton pump inhibitor or a histamine 2 (H2) blocker.
The third-generation oral NK1 receptor antagonist rolapitant (Varubi) was approved in September 2015. Its 180-hour half-life allows it to be dosed just once per cycle, without adjusting the dose of dexamethasone. In the global trial of 1,087 patients, rolapitant provided complete delayed emesis protection in 71% of patients, vs 60% of active controls (P = .0001).5
Dr. Holmes emphasized the value of olanzapine on this list. “Olanzapine, an atypical antipsychotic, is very active, especially for breakthrough nausea and vomiting, because it targets many receptors and blocks multiple neurotransmitters,” she said.
The National Comprehensive Cancer Network® (NCCN®) guidelines allow olanzapine to be substituted for an NK1 receptor antagonist in patients receiving highly emetogenic chemotherapy and moderately emetogenic chemotherapy—and for breakthrough emesis, 10 mg on days 1 to 4—and is a much less expensive treatment option, she added.
“Treating anticipatory nausea and vomiting with benzodiazepines, such as lorazepam, is also very important for some patients,” Dr. Holmes said.
Choosing Therapy Wisely
Finally, Dr. Holmes emphasized the need to personalize antiemetic therapy. Although a “zero tolerance” policy should guide treatment, patients should be “at high-enough risk” for these drugs, she said, “first do no harm (with unnecessary medications).”
For the appropriate patients, she said, “use the most effective drugs at the lowest dose and know their side effects…. Personalize therapy by addressing the extrinsic factors (treatment-related emetogenic grade) and intrinsic factors (patient’s own risk factors, including gastroesophageal reflux disease and a diet of hot, spicy foods).”
Dr. Holmes dispelled the myth held by some physicians that “side effects show that the treatment is working,” or that “the patient will tell me if she or he is having side effects,” which leads many patients to remain inadequately treated. “Adherence to antiemesis guidelines is not very good, especially with highly emetogenic chemotherapy,”6 she lamented. “If you do adhere to the guidelines, you have better control over nausea and vomiting, but choosing wisely is using what you need—and nothing more.” ■
Disclosure: Dr. Holmes reported no potential conflicts of interest.
References
1. Holmes FA: Emesis and myelosuppression. 14th Annual School of Breast Oncology. Emory University, Atlanta. Presented November 4, 2016.
2. Sustol (granisetron) extended-release injection package insert. Heron Therapeutics, August 2016. Available at http://www.sustol.com/public/pdfs/PI.pdf. Accessed November 16, 2016.
3. Boyer EW, Shannon M: The serotonin syndrome. N Engl J Med 352:1112-1120, 2005.
4. Sim SS, Sun JT: Ocular flutter in the serotonin syndrome. N Engl J Med 375:e38, 2016.
