Increased awareness, new therapies may alleviate ‘pervasive problem’ of CINV
Nausea and vomiting are two of the most distressing and potentially debilitating effects of cancer treatment.
They also are among the most common. Prospective studies suggest incidence of chemotherapy-induced nausea and vomiting (CINV) exceeds 60%.
“Most of the drugs we use in cancer chemotherapy produce some degree of nausea or vomiting,” Lee S. Schwartzberg, MD, FACP, division chief of hematology and oncology at The University of Tennessee Health Science Center, as well as president and chief medical officer of The West Clinic in Memphis, Tennessee, told HemOnc Today. “Many of the common drugs we use are categorized as moderate emetogenic chemotherapies, which means there is a 30% to 90% chance of experiencing nausea and/or vomiting without preventive therapy.”
Researchers have long sought effective antiemetic therapies. Most studies have focused on neurokinin-1 (NK-1) receptor antagonists, which can reduce CINV when added to the serotonin and dexamethasone backbone of most chemotherapies.
The FDA approved three agents in the past 2 years that have shown promise for CINV control. Despite their potential, no agent has proven 100% effective.
Also, research suggests antiemetics are not consistently administered according to guidelines. Clinicians may not fully understand the potential severity of CINV, putting patients’ quality of life at risk and jeopardizing treatment compliance if symptoms become too severe.
“Our goal in recent years has been to try to prevent CINV completely,” Schwartzberg said. “We hope that the introduction of new drugs and the awareness — or re-awareness — surrounding the condition will lead to better guideline compliance and greater physician appreciation of this difficult side effect.”
HemOnc Today spoke with clinicians and researchers about the impact CINV has on patients; the potential of emergent antiemetic therapies; and the need for oncology professionals to better understand the risks and adhere to guidelines.
Impact of CINV
Cytotoxic chemotherapies — such as cisplatin — administered without prophylactic antiemetic therapy have a greater than 90% chance of causing CINV. Carmustine and dacarbazine also are highly emetogenic.
The side effect can be costly.
Burke and colleagues retrospectively assessed CINV–associated health care costs among 19,139 patients who received their first cycle of moderately or highly emetogenic chemotherapy in a U.S. outpatient setting. Patients received CINV prophylaxis with a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist (85%), dexamethasone (76%) or NK-1 antagonist (2%).
Results, published in Supportive Care in Cancer, showed 13.8% had a CINV–associated health care visit. Most of these patients (64%) required inpatient treatment, whereas 26% received outpatient treatment and 10% received treatment in the ED. Mean costs of CINV visits were $7,448 for those who required inpatient treatment, $1,494 for those who had outpatient visits and $918 for those who had ER visits.
Despite the physical, emotional and financial toll, however, some oncologists may not fully understand the extent to which nausea and vomiting affect their patients.
Morin and colleagues surveyed 75 oncologists, 35 oncology nurses and 77 patients to evaluate perceptions of chemotherapy- or radiation-induced nausea and vomiting. Results showed oncologists tended to overestimate incidence of these events but underestimate their impact on patients’ quality of life.
“I don’t like the term CINV,” Mark G. Kris, MD, William and Joy Ruane chair in thoracic oncology at Memorial Sloan Kettering Cancer Center, told HemOnc Today. “Most doctors don’t really know what it means. I think it is something that pharmaceutical companies have constructed. I prefer to call it ‘cancer nausea’ or ‘vomiting caused by cancer treatment,’ because I feel it reflects the situation more accurately.”
There are several stages to CINV, according to the Oncology Nursing Society.
Patients may experience acute CINV, which occurs within 24 hours of chemotherapy receipt, or delayed CINV, which occurs up to 7 days after treatment.
Patients who develop CINV or other adverse events may subsequently experience anticipatory vomiting, a conditioned response that causes a person to feel nauseous or emit prior to their next chemotherapy dose. Thirty percent of patients who have nausea and 20% who vomited after previous chemotherapy develop anticipatory CINV.
Other concerns include breakthrough CINV — the presence of nausea or vomiting despite prophylactic treatment — or refractory CINV, which occurs when a patient no longer responds to prophylaxis or medications used to control breakthrough CINV symptoms.
Patients often are reluctant to initiate chemotherapy because of their fear of CINV, David L. Jennings II, MSN, RN, AGPCNP-BC, oncology nurse practitioner at Levine Cancer Institute at Carolinas HealthCare System, as well as a HemOnc Today Editorial Board member, said in an interview.
“CINV can affect a patient’s nutrition, energy levels, toileting habits, mental health, quality of life and even their overall survival,” Jennings said. “It can be extremely distressing for patients, as well as caregivers. Sometimes, even our best attempts to prevent CINV with multiple antiemetics and other supportive medications fail, resulting in increased office visits, supportive infusions and hospitalization.”
In the Morin analysis, 51% of patients did not report CINV symptoms because they considered them a normal consequence of cancer treatment. Sixty-eight percent of patients reported noncompliance to their antiemetic therapies. Common reasons for lack of adherence were the number of drugs required and concern that swallowing antiemetic therapies actually would cause nausea and vomiting.
“Most people remember the last time they vomited. That is how disruptive it is,” Kris said. “Patients with cancer have that same feeling and that same concern. There is something about this action that is very jarring.”
The European Society for Medical Oncology, Multinational Association of Supportive Care in Cancer and ASCO each have antiemesis guidelines.
Last year, ASCO released a focused update on their guideline on antiemetic research and treatment to reflect new research. The guidelines recommend all patients undergoing highly emetogenic chemotherapy should be offered a three-drug combination that includes an NK-1 receptor antagonist, a 5-HT3 receptor antagonist and dexamethasone.
“It was ASCO’s wish to address something that is so vitally important to the cancer community, both to patients and to physicians, and to address something that is such a pervasive issue,” Kris, one of the guideline authors, said.
Despite the prevalence of guidelines, data suggest adherence is low.
“Many physicians continue to prescribe anti-sickness drugs outside of guidelines, despite knowledge of the guidelines,” Mark Clemons, MD, FCRP(UK), professor of medicine at University of Ottawa and associate scientist in the cancer therapeutics program at Ottawa Hospital Research Institute, told HemOnc Today. “My major concern is that guidelines ignore all personal risk factors for emesis. These may include younger age, type of chemotherapy, prior emesis, or a history of travel sickness or prior morning sickness in pregnancy.”
Gilmore and colleagues analyzed compliance with NCCN guidelines in U.S. community oncology practices. They determined the rate of guideline-consistent CINV prophylaxis was 57.3%. Patients who received guideline-consistent treatment were more likely to be CINV free during the 5 days after chemotherapy (53.4% vs. 43.8%; OR = 1.31; 95% CI, 1.07 to 1.69).
Aapro and colleagues assessed chemotherapy-naive patients who initiated highly or moderately emetogenic chemotherapy. They determined adherence to guidelines to prevent CINV was 55% during the acute phase, 46% during the delayed phases and 29% for the overall study period. Patients who received guideline-compliant treatment were more likely avoid emesis and use of rescue therapy (OR = 1.43; 95% CI, 1.04-1.97).
Guideline adherence tends to be lower in the delayed phase. An underestimation of delayed emesis, as well as the fact up to 50% of patients still experience delayed emesis despite treatment, may contribute to this, according to a review published in 2009 in Journal of the National Comprehensive Cancer Network.
Appropriate treatment of delayed CINV is crucial, Kris said.
“It does not matter what day CINV occurs. If it disrupts your life, it is important,” he said. “In fact, the nausea that occurs days later, when you are not in a health care facility and with a nurse, can be more disruptive and not make sense to the patients.”
Even with guideline compliance, nausea can be a substantial concern.
“When we look at our own internal data, we see people getting all the right antiemetics, and half of them still experience some nausea,” Kris said. “You might not vomit — but if the nausea is debilitating, it keeps you from living normally. By the perception that chemotherapy causes this, and the reality that nausea is a pervasive problem, that is a place where patients really feel it.”
Therapies have reduced by up to 80% the occurrence of vomiting from treatment with an anthracycline and cyclophosphamide, Paul J. Hesketh, MD, professor of medicine at Tufts University School of Medicine and chair of Lahey Hospital & Medical Center in Burlington, Massachusetts, told HemOnc Today.
“We have gotten better at controlling vomiting than controlling nausea,” Hesketh said. “There can be up to 60% of patients who really have no problem with vomiting or with nausea with this kind of chemotherapy regimen. However, that leaves up to 40% who will still have some degree of CINV — and this is from studies where really optimal conditions have been used.”
More study should specifically be directed at controlling nausea, Clemons said.
“We need better drugs, and we need trials that specifically measure nausea,” he said. “For the patients I treat, nausea — not vomiting — is often the major issue they face.”
The field of CINV medical research has been prominent since the 1980s, starting with a focus on the 5-HT3 receptor antagonist, Kris said.
“Ondansetron and palonosetron became some of the most widely used drugs,” he said. “Next, there was the discovery that dexamethasone was a helpful addition.”
Since the routine inclusion of dexamethasone in CINV treatment, considerable research has focused on the use of NK-1 receptor antagonists in prophylaxis. These drugs prevent substance P — which can mediate the induction of vomiting pathways — from binding to the NK-1 receptor.
“NK-1 antagonists improve the control of CINV, plain and simple,” Schwartzberg said. “These are drugs in our armamentarium that will really reduce the burden of becoming nauseated and vomiting.”
In 2003, aprepitant became the first oral NK-1 receptor antagonist specifically approved to control CINV.
The FDA approved the drug based in part on a double blind, randomized controlled study by Hesketh and colleagues, who assessed the addition of aprepitant to standard therapy with ondansetron and dexamethasone among patients who received high-dose cisplatin chemotherapy. Complete response — defined as no emesis and no rescue therapy — on days 1 through 5 after cisplatin served as the primary endpoint.
Results showed more patients who received aprepitant achieved complete response (72.7% vs. 52.3%; P < .001).
Time to first emesis after chemotherapy also was significantly longer with aprepitant.
“Aprepitant’s approval was important and led to better patient care,” Clemons said. “However, as more studies have been performed, we have realized that more new drug combinations and new treatments are needed.”
There also are challenges with aprepitant.
“It’s a short-acting drug, given orally 3 days in a row, so it is not the most convenient drug,” Schwartzberg said. “There is an IV form of aprepitant called fosaprepitant [Emend for Injection, Merck]. One dose of fosaprepitant IV is equivalent to the 3-day oral dosing, so that’s frequently used.”
Weinstein and colleagues conducted a double blind, randomized phase 3 trial to compare IV fosaprepitant with placebo in adults receiving nonanthracycline and cyclophosphamide-based moderately emetogenic chemotherapy. Results showed more patients assigned fosaprepitant did not experience delayed CINV (78.9% vs. 68.5%; P < .001) and overall CINV (77.1% vs. 66.9%; P < .001).
A greater proportion of patients assigned fosaprepitant did not experience any vomiting (82.7% vs. 72.9%; P < .001) or significant nausea (83.2% vs. 77.9%; P = .03). However, fosaprepitant did not reduce the occurrence of CINV in the acute phase (93.2% vs. 91%).
Based on these results, the FDA in February approved fosaprepitant for use in combination with ondansetron and dexamethasone for the control of CINV after moderately emetogenic chemotherapy.
In a double blind, randomized controlled trial — published in March in The Lancet Oncology — Ruhlmann and colleagues evaluated fosaprepitant for CINV control in patients undergoing 5 weeks of chemoradiotherapy for cervical cancer.
The researchers randomly assigned 234 patients IV fosaprepitant (n = 118) or placebo (n = 116) during chemoradiotherapy. A greater proportion of patients assigned the active agent experienced no emesis during chemoradiotherapy (65.7% vs. 48.7%), and they demonstrated a significantly lower cumulative emesis risk (subhazard ratio = 0.58; 95% CI, 0.39-0.87).
“Given the minimal incremental toxic effects from the antiemetic regimen, it is reasonable to consider extrapolating the data to other higher-risk chemoradiation-induced nausea and vomiting settings, including upper abdominal radiation with combined chemotherapy for gastric, esophageal or pancreatic cancers,” Schwartzberg wrote in an editorial that accompanied the study. “... [This trial] brings us one step closer to the ultimate goal of delivering complex combined-modality chemoradiotherapy regimens without side effects.”
Trial designs questioned
Two other NK-1 receptor antagonists — rolapitant (Varubi, Tesaro) and combined netupitant/palonosetron (Akynzeo; Eisai, Helsinn) — received FDA approval in the past 2 years.
The netupitant and palonosetron combination has shown efficacy for CINV prevention in the acute and delayed settings. In a clinical trial, 98.5% of patients assigned the therapy did not experience any vomiting or require any rescue medication in the acute setting. These rates extended to 90.4% in the delayed setting and 89.6% overall.
“It is important for drugs like netupitant to be approved,” Kris said. “It fosters a greater interest in this area: As drugs are rolled out, it reminds doctors of the importance of this problem and it gives them choices. For a very long time, not many people were really interested in this field. We hope this will rekindle interest.”
“There had not been a new CINV drug for several years [until netupitant was approved],” Schwartzberg said. “A bit of complacency crept into the treatment or prevention of CINV, yet we know from clinical trials and from our own clinical experience that there is a residual unmet need among patients receiving chemotherapy.”
Two randomized controlled phase 3 trials conducted by Rapaport and colleagues and published in The Lancet Oncology helped lead to rolapitant’s approval. Patients receiving cisplatin-based chemotherapy were assigned 180 mg of a 5-HT3 receptor antagonist and dexamethasone with rolapitant or placebo. In these trials, researchers defined complete response as no emesis and no use of rescue therapy.
In both trials, a significantly larger proportion of patients assigned rolapitant achieved a complete response in the delayed phase (trial 1, 72.7% vs. 58.4%; P < .001; trial 2, 70.1% vs. 61.9%; P = .043).
In a third trial, Schwartzberg and colleagues enrolled patients receiving a variety of moderately emetogenic chemotherapies, including anthracyclines and cyclophosphamide. Results, also published in The Lancet Oncology, showed more patients assigned rolapitant achieved a complete response (71.3% vs. 61.6%; P < .001).
However, there may be potential flaws in the design of these trials, Ian Olver, MD, of Sansom Institute for Cancer Research at University of South Australia, suggested in an accompanying editorial.
“A trial comparing rolapitant and the shorter-acting NK-1 receptor antagonists is necessary,” Olver wrote. “Combinations with palonosetron would also be instructive. It would be advantageous if such combinations could enable a reduction in the high doses of steroids that are part of current antiemetic regimens. ... Although these three studies show that rolapitant improves efficacy, particularly in the delayed phase of emesis with moderately and highly emetogenic chemotherapy, rolapitant’s place in routine antiemetic care is yet to be determined.”
“The randomized controlled trials in which rolapitant was studied showed positive results compared with the control arms, but clinicians should be aware that rolapitant was compared with placebo in all three trials,” Jennings said. “The addition of rolapitant to antiemetic regimens could ultimately result in less CINV, but the study designs somewhat limit the significance of the trial data.”
There are many different combinations of antisickness drugs, and their efficacy needs to be confirmed, Clemons said.
“There are far too many studies using far too many endpoints to compare far too many different combinations of these antisickness drugs,” he said.
In light of FDA approvals, more comparative trials are needed, Hesketh said.
“Comparative data are definitive to determine why one agent may be preferred,” he said. “Rolapitant provides another safe and effective option, but it is now up to providers — based on finances and other issues — to decide which agent they are going to recommend whenever an NK-1 receptor antagonist is indicated.”
Future of CINV
The spike in approvals for — and results of research into CINV — necessitates patient and provider education.
“There was a time in the 1990s when you couldn’t go to a medical meeting without encountering a discussion of these agents,” Hesketh said. “Now that there are new NK-1 receptor antagonists coming out, there will be an imperative to [again] create more of a buzz to educate physicians as to what constitutes appropriate use of these agents, and what the best evidence-based guidelines say.”
Although ASCO guidelines were just updated, they are undergoing another revision to reflect the most recent drug approvals, Kris said.
Hesketh — co-chair of the ASCO antiemetic guideline panel — hopes another update will be published later this year.
“We want to come forward with a more definitive, complete guideline that will reflect everything that has happened in the field over the past 4 years,” Hesketh said. “We are looking at all situations, and that process is just beginning.”
Updated guidelines should provide more data on the need to approach CINV treatment on a case-by-case basis, Jennings said.
“Clinicians need to provide optimal care based on current evidence,” Jennings said. “The latest advances in CINV should be included in the updated guidelines and recommendations. Current antiemetic standards of care work well for some, but others need a more individualized regimen.”
Overall, the increased interest in CINV will lead to better patient and provider education, which has the potential to improve care, Schwartzberg said.
“Knowledgeable patients are great team members in shared decision-making and, in a busy practice, sometimes things can fall through the cracks,” he said. “A two-way relationship, and the engagement of patients, can only help.”
Education programs for new CINV therapies should allow for discussion of different tools available, Kris said.
“If nothing else, it will give hope to our patients that we are working in this field and that we will get it right,” he said. “We need education for the doctors to prescribe the medicine, and for the patients to know why they should continue to take them religiously, even when they are feeling well.” – by Cameron Kelsall
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For more information:
Mark Clemons, MD, FRCP(UK), can be reached at firstname.lastname@example.org.
Paul J. Hesketh, MD, can be reached at email@example.com.
David L. Jennings II, MSN, RN, AGPCNP-BC, can be reached at firstname.lastname@example.org.
Mark G. Kris, MD, can be reached at email@example.com.
Lee S. Schwartzberg, MD, FACP, can be reached at firstname.lastname@example.org.
Disclosure: Hesketh reports unpaid consultant roles with Helsinn and Tesaro. Schwartzberg reports consultant roles with Helsinn and Tesaro, as well as an investigator role in the phase 3 trials of rolapitant. Clemons, Jennings and Kris report no relevant financial disclosures.
Should behavioral therapy be used as the primary treatment to control anticipatory vomiting?
Antiemetics, including the new 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, do not adequately control anticipatory nausea and vomiting (ANV). Behavioral interventions, based on well-established learning theory, can be uniquely effective as an adjunct approach in mitigating these side effects.
ANV develops in approximately 30% of patients by the fourth treatment cycle and has been shown to be linked to psychological, neurologic and physiologic factors. ANV is best conceptualized as a conditioned response, which means patients learn to associate stimuli and situations connected with the administration of chemotherapy with the negative physical effects of the treatment itself. Hence, merely thinking about, seeing or experiencing the chemotherapy setting can elicit ANV.
ANV is treatable through four main behavioral interventions that reduce the anticipatory anxiety and thoughts that evoke ANV. When used in conjunction with the initial chemotherapy session, the inclusion of behavioral techniques can serve a preventive role, helping to forestall or diminish the development of aversive symptomatic reactions.
Perhaps the simplest and most cost-effective approach involves progressive muscle relaxation training (PMRT), which trains patients to achieve a state of muscle relaxation in anticipation of situations that produce tension or anxiety, such as undergoing chemotherapy. PMRT involves learning to relax by alternatively tightening and then relaxing specific muscle groups in a progressive manner. This method often is combined with guided imagery in which the individual visualizes pleasant, soothing images or scenes while relaxed. PMRT is typically taught to patients in a single session and then patients practice the technique at home using an audiotape or a set of written instructions.
Systematic desensitization involves replacing the maladaptive response of ANV that occurs over time in response to stimuli — such as the clinic, the nurse and other chemotherapy experiences — with an anxiety-inhibiting response such as muscle relaxation. Specifically, the patient is instructed to construct a hierarchy of stimuli that elicit ANV, and under a relaxed state, imagine moving progressively closer to the setting where the chemotherapy is administered, thereby lessening the psychological impact of the clinic setting and replacing it with more positive affective responses.
Hypnosis is a self-control technique in which patients learn to invoke a physiologic state incompatible with ANV. The technique involves inducing a state of body relaxation, followed by presentation of restful psychic imagery; while hypnotized, patients are given suggestions such as undergoing chemotherapy in a relaxed state, which can also be coupled with systematic desensitization.
Cognitive distraction trains patients to focus their attention away from nausea and vomiting through a variety of techniques, such as using video games. This is considered an especially effective alternative for pediatric patients, who sometimes have difficulty mastering other techniques.
There are a variety of behavioral therapy techniques that have shown proven efficacy in reducing ANV, in both adults and children. These techniques are the cornerstone of learning theory interventions for anticipatory anxiety and related physical symptoms and can be readily taught to patients by nonspecialized personnel. Given the importance of maintaining quality of life and reducing stress in promoting adherence and optimal health outcomes, the integration of patient-centered behavioral and pharmacologic approaches should be strongly considered by the clinical team.
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Suzanne M. Miller, PhD, is director of the Psychosocial and Behavioral Medicine Program and professor of cancer prevention and control at Fox Chase Cancer Center/Temple University Health System. She can be reached at email@example.com. Disclosure: Miller reports no relevant financial disclosures.
If chemotherapy-induced nausea and vomiting (CINV) is effectively controlled with therapies during the first cycle of chemotherapy, the patient is likely to have effective control during subsequent cycles of the same chemotherapy.
Patients who experience CINV after their initial courses of chemotherapy may develop a conditioned response known as anticipatory nausea and vomiting (ANV) before the administration of chemotherapy in future chemotherapy cycles. This is attributed to the adverse memory of their poor experience with previous chemotherapy.
The predominant factors related to ANV are classical conditioning, demographic factors (age less than 50 years, female sex), emetogenicity of the chemotherapy, anxiety and negative expectations. Incidence rates for this type of nausea and vomiting range from 10% to 45%, with nausea occurring more frequently. ANV can be triggered by a variety of odors of the clinic or treatment areas; nurses who have administered the chemotherapy; and sights, thoughts or anxiety associated with the chemotherapy treatment. It is more challenging to control and treat than acute or delayed CINV, which occurs 1 to 5 days after chemotherapy.
If the patient has a poor experience with CINV in the first cycle, it may be more difficult to control CINV in subsequent cycles, and ANV may develop.
To prevent ANV, patients should be counseled about their expectations of CINV before the initial course of treatment. Patients should be informed that very effective prophylactic antiemetic regimens will be used and that 70% to 75% of patients have a complete response — no emesis and no use of rescue medications. For optimum control of CINV during the first course of chemotherapy, each patient should receive the most effective prophylactic antiemetic regimen based on the specific type of chemotherapy and their individual risk factors. International guidelines recommend very specific antiemetic agents based on the emetic risks of each type of chemotherapy. This approach will decrease the negative expectations of patients and may decrease the incidence of ANV.
The earlier ANV is identified, the more likely treatment will be effective. The use of antianxiety medications, such as lorazepam or another benzodiazepine, may be considered for excess anxiety prior to the first course of chemotherapy to obtain an optimum outcome and prevent ANV.
If ANV occurs despite the use of guideline-directed prophylactic antiemetics, additional or different antiemetic drugs may or may not be effective. Behavioral or psychological interventional therapy could be considered, and a number of behavioral interventions have been investigated.
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Rudolph M Navari, MD, PhD, is director of the Cancer Care Program of Central and South America at WHO and professor of medicine at Indiana University School of Medicine South Bend. He can be reached at: firstname.lastname@example.org. Disclosure: Navari reports no relevant financial disclosures.