Evolving strategies for the elimination of nausea and vomiting are making treatment more comfortable for many patients with cancer.
CHRYSTINE TEDESCHI is glad that treatment for CINV has advanced since she experienced the side effect during cancer treatment in 1998. PHOTO BY TESSA CONNELLY
Karin Marzilli had six rounds of chemotherapy, along with radiation, to treat her stage 3b lung cancer. Her doctors at the Comprehensive Cancer Center at Miriam Hospital in Providence, Rhode Island, treated her with an intravenous antiemetic before giving her chemotherapy, and that was good enough at first, recalls Marzilli, 57.
“I tolerated my chemo drugs really well at the beginning,” the Rhode Island resident says. “But after the fourth and fifth rounds, I could tell that I wasn’t right in the morning. I didn’t want to eat or drink.”
She talked to her doctor and was prescribed Compazine (prochlorperazine) and Zofran (ondansetron), which she could take in alternating doses when she felt nauseated.
“I never vomited,” Marzilli says. “If you get ahead of it, you don’t have to experience bad nausea and vomiting.”
That’s exactly what antiemetics experts want patients to know: Although 80 percent of patients who get chemotherapy would otherwise experience chemotherapy-induced nausea and vomiting (CINV), this side effect can often be stopped before it begins with a group of medications known as antiemetics. These drugs can also ease CINV in patients taking targeted drugs or radiotherapy.
THE EVOLUTION OF CINV
According to medical oncologist Lee Schwartzberg, executive director of the West Cancer Center in Memphis, Tennessee and chief of the University of Tennessee Health Science Center’s Division of Hematology and Oncology, nausea and vomiting are reactions that nature has provided for our protection.
“For example, if we eat a bad berry, our body is designed to get rid of it,” he says. “We have receptors in our GI (gastrointestinal) tract, and when a toxin hits those receptors, they send a message to the brain. The brain then triggers nausea and vomiting to rid the body of the toxin.”
But this natural response, which in most circumstances serves us well when we ingest a toxin, can be problematic for those whose cancer is being treated with chemotherapy or other types of treatments that can cause nausea and vomiting. Indeed, CINV can affect everything from nutrition and hydration to a person’s emotional health and ability to carry on with daily activities.
That can be a worrisome prospect, but the truth is that many won’t experience it. Schwartzberg wants patients and their families to know it’s a myth that everyone who receives chemotherapy will automatically experience nausea and vomiting. “Our goal is to make sure no patient is sick,” he says, adding that, for the most part, preventive antiemetics are used in any patient who faces a risk of this side effect.
In past decades, that kind of a goal would have seemed like an impossibility, noted Jean-Louis Misset, a Parisian professor of oncology, in a 2007 paper.
In the 1970s, according to Missett, CINV was largely uncontrolled in patients receiving chemotherapy, and in a 1983 survey, this grueling side effect was rated as the most distressing of those associated with chemotherapy. Hope emerged as a result of work by several investigators — among them Richard Gralla, an oncologist and current professor of medicine at Albert Einstein College of Medicine. In a 1981 paper, Gralla wrote that he had been able to control CINV even in patients taking high-dose cisplatin, one of the most nausea-inducing chemotherapies, by using very high doses of metoclopramide, which is indicated for heartburn, reflux and to slow gastric emptying when that process causes nausea or vomiting. Gralla’s treatment was complicated, though, by the fact that it had to be given every two hours, and that it caused side effects.
As the 1980s moved along, Misset pointed out, a greater understanding of the mechanisms of CINV led to the development of a class of drugs called setrons, and relief for many patients.
“It’s a lot better now than it was 25 or 30 years ago,” says Barbara Todaro, a doctor of pharmacy who serves as resource director of the Investigational Drug Service at Roswell Park Cancer Institute in Buffalo, New York, and as a member of the National Comprehensive Cancer Network’s Antiemetic Panel. “With (new-generation) antiemetics, we’ve been able to greatly reduce acute nausea and vomiting during chemotherapy treatment, and help manage delayed nausea and vomiting.”
When it comes to evaluating patient risk for developing CINV, a number of factors must be considered. First, says Schwartzberg, are demographic factors. He says that women have a greater tendency to develop CINV, as do individuals under the age of 50. Additional risk factors include a patient’s history with motion sickness, any history of morning sickness during pregnancy, and any previous history of CINV with cancer treatment. Patients who routinely drink a lot of alcohol are less likely to experience CINV than are teetotalers.
Ultimately, however, the biggest risk factor for developing CINV is the type of chemotherapy drug — or combination of drugs — used during treatment.
“Not all chemotherapy is created equal when it comes to nausea and vomiting,” says Todaro. Certain chemotherapy drugs are considered highly emetogenic (more likely to cause CINV), particularly those most likely to be used to treat lung, breast and gynecological cancers, as well as leukemia, she says.
Among the most emetogenic drugs are cisplatin, followed by moderately emetogenic drugs such as the anthracycline doxorubicin and the alkylating agent cyclophosphamide, both of which are commonly used in treating breast cancer, says Schwartzberg. All chemotherapy drugs are rated by the American Society of Clinical Oncology (ASCO) according to their risk of causing emesis, labeled as minimal, low, moderate or high.
Targeted cancer drugs and radiotherapy techniques are labeled according to that system, too. Patients taking targeted drugs are treated for nausea and vomiting with the same regimens as patients getting chemotherapy; those getting radiation take the same drugs, but perhaps on different schedules.
Both Schwartzberg and Todaro emphasize that it’s important to fit the prevention strategy to the potential risk. “Patients new to the cancer experience are often surprised to learn that there’s something we can do about nausea and vomiting,” says Schwartzberg, adding that decisions about antiemetic treatments are made mainly based on the chemotherapy drug that a patient is taking. “Our goal is to make sure patients get a full dose of chemotherapy, on schedule, to get the maximum benefit.”
At the same time, doctors must prescribe antiemetics with care, because they can cause side effects that — although infrequently — can outweigh their benefits.
A SCIENCE AND AN ART
Treating CINV with antiemetics is both science and art. Based on patient risk factors and on the chemotherapy drug the patient is taking, doctors decide at the outset on a prevention strategy. The goal, says Todaro, is to prevent nausea and vomiting to begin with — a goal she says is often achievable with the right antiemetics.
CINV is classified into different categories. Acute CINV occurs within 24 hours of receiving chemotherapy treatment, while delayed CINV occurs at least 24 hours after a patient receives chemotherapy up to approximately seven days post-treatment. Anticipatory CINV, which typically occurs prior to the beginning of chemotherapy treatment, is most common in patients who have experienced nausea and vomiting during past treatments.
“We do pretty well with (medically controlling) acute nausea and vomiting,” Todaro says, referring to CINV that begins within the first 24 hours of chemotherapy treatment. But delayed CINV can be more challenging.
Most beneficial in preventing CINV in the acute phase is a class of antiemetic drugs known as 5-HT(3) receptor antagonists — a class of drugs that Schwartzberg refers to as the “setrons class.” These drugs affect receptors in the stomach and brain, blocking the action of serotonin and dampening the nausea and vomiting response.
The most commonly prescribed 5-HT(3) receptor antagonists include Anzemet (dolasetron), granisetron, Zofran (ondansetron) and Aloxi (palonosetron). Typically, 5-HT(3) receptor antagonists are quite effective in preventing acute CINV at the start of a patient’s chemotherapy treatment, says Schwartzberg.
The most common side effects of these drugs are lightheadedness, constipation, headache, blurred vision, mental status changes and fever.
Delayed CINV tends to be more effectively treated by a second group of antiemetics known as neurokinin 1 (NK1) receptor antagonists. These drugs, says Schwartzberg, affect a different receptor — found in the brain — than the 5-HT(3) receptor antagonists do. These drugs include oral Emend (aprepitant) or the intravenous formulation of that drug, fosaprepitant; Varubi (rolapitant), an oral drug that was approved by the U.S. Food and Drug Administration (FDA) in 2015; and Akynzeo (NEPA), an oral combination drug comprised of the NK1 antagonist netupitant and the 5-HT(3) receptor antagonist palonosetron.
Side effects of this class of drugs can include hiccups, dizziness, mouth sores, low blood cell counts and digestive problems or stomach pain.
The NK1 receptor antagonists tend to be good choices for treating delayed CINV because they add little toxicity and are typically long-acting, Schwartzberg says. Still, he adds, despite advances in each class of antiemetics, effectively treating CINV in some patients may require a combination of drugs. For example, breast cancer patients being treated with highly emetogenic chemotherapy drugs might require a cocktail of three agents: a 5-HT(3) receptor antagonist, an NK1 receptor antagonist and a corticosteroid, such as prednisone or Decadron (dexamethasone). Such combinations work to eliminate vomiting in almost all patients, according to Schwartzberg, who adds that “80 to 90 percent will have no vomiting, even if they have highly emetogenic drugs.”
Such “multiple mechanisms” can be effective in preventing CINV in patients being treated with more highly emetogenic drugs, agrees Todaro. Adding additional drugs from a different class can also be effective for patients who experience “breakthrough” nausea and vomiting, meaning CINV that emerges in a patient who is already taking antiemetics, either at the beginning of therapy or later in the course. These additional drugs are often referred to as “rescue” medications.
Todaro suggests that those patients speak to their doctors or pharmacists about their breakthrough CINV. “We need to know if it’s not working,” she says.
WHEN CINV REMAINS RESISTANT
Helpful in serving a variety of patient needs is that different antiemetics can be delivered via different methods — for example, orally, as a liquid, as a standard pill or, if nothing is tolerated by mouth, one that dissolves under the tongue; through a patient’s IV; as a suppository; or as a patch on the skin. Patients whose nausea and vomiting is well controlled may have no trouble taking pills or liquid medications, while patients whose nausea and vomiting is not well controlled may struggle with taking an antiemetic orally. Patients who can’t keep pills or liquids down may also be at risk for dehydration and other problems, so they should speak with their doctors about other medications or other ways of taking medications.
But what can be done for patients who have successfully kept down their medications but have not responded to either setrons and NK1 drugs?
Cannabinoids, an active group of ingredients in marijuana, are sometimes used to help ease CINV in these patients. A prescription medication that contains cannabinoids, Marinol (dronabinol), is approved by the FDA to treat CINV. Also approved for CINV that has not responded to other drugs is the oral synthetic cannabinoid medication Cesamet (nabilone). Side effects can include increased heart rate, decreased blood pressure and drowsiness.
Marijuana itself is available medicinally in some states, but patients may need to go to extra lengths in order to get it, such as finding the rare doctor willing to recommend it and then signing up with the state in which they live as someone who’s eligible to take the drug.
Chrystine Tedeschi, 63, of Williamsville, New York, says she’s been amazed at how far treatment has come since she was diagnosed with stage 3c ovarian cancer and treated in 1998. Tedeschi, who was treated post-surgery with 10 rounds of cisplatin and six rounds of paclitaxel, says her nausea and vomiting were terrible, leading to a significant loss of weight and muscle mass. She was initially treated with prochlorperazine, an antipsychotic medication sometimes used to treat CINV, which helped control her vomiting, but not her nausea.
Today, Tedeschi, who’s had no recurrence of cancer since being treated, talks to many women undergoing treatment in her role as a regional coordinator for the ovarian cancer helpline at SHARE, a group that offers support to women with breast or ovarian cancers. She says that combinations of antiemetic medications have been quite effective for some patients — quite a few of whom report experiencing no nausea and vomiting at all during chemotherapy.
“It’s been thrilling for me to see that women are not suffering in the same way I did,” she says.
NEW STRATEGIES FOR TREATING CINV
As patient needs continue to evolve, so, too, do the antiemetics used to treat CINV. Newer medications may help to better address nausea, particularly delayed nausea. One such antiemetic with promise in treating delayed CINV is the granisetron patch, which offers prolonged release, says Schwartzberg. But, he adds, the medication takes “a while” to get into the bloodstream when administered via a patch.
Also promising in treating acute and delayed CINV is APF530, which has not yet received FDA approval. Schwartzberg says the injection of granisetron offers a high level of medication right after injection, followed by a sustained release. A recent phase 3 clinical trial of APF530 versus Zofran, each with an NK1 antagonist and a corticosteroid, found that a single injection of APF530 maintained therapeutic levels of granisetron for at least five days in cancer patients receiving highly emetogenic cisplatin-based chemotherapy, and that it achieved a higher rate of complete response in these patients.
Both Schwartzberg and Todaro mentioned the use of “off-label” medications such as olanzapine, an antipsychotic drug with very few side effects. “Olanzapine is very effective,” Schwartzberg says. “It hits many neurotransmitters and can replace the NK1. It’s more commonly used as a rescue medicine for patients who still get CINV after other meds.” In addition, this drug and prochlorperazine are effective in treating breakthrough CINV when used in combination with other antiemetics.
Side effects of olanzapine include fatigue and a sedating effect, says Todaro.
Ultimately, it’s important to know that there are many medications that can be used alone or in combination, and delivered by a variety of methods, to effectively combat CINV — and that communicating with your doctor is an important part of managing nausea and vomiting.
“I don’t think the message has fully gotten out that we have really good prevention strategies,” says Schwartzberg. “Don’t be afraid to talk to your doctor. Supportive care measures are very good, and they’re very varied.”