For patients with cancer, chemotherapy-induced nausea and vomiting (CINV) can strike a major blow to quality of life. Sometimes, it can become so severe that patients are reluctant to continue treatment.
Now, results from a large double-blind, randomized, phase 3 study demonstrate that adding the antipsychotic medication olanzapine (Zyprexa Relprevv, Eli Lilly) to the standard triple-drug antiemetic regimen could offer physicians and their chemotherapy patients more choices and better management of CINV.
Olanzapine was added to a standard antiemetic regimen containing an NK1-receptor antagonist (aprepitant or fosaprepitant), a 5-HT3-receptor antagonist (such as ondansetron), and dexamethasone (Baycadron, Wockhardt). It was more effective than placebo when combined with these agents for the prevention of nausea and vomiting in patients with no previous chemotherapy who are receiving highly emetogenic chemotherapy, concludes a report published onlineJuly 13 in the New England Journal of Medicine.
"This drug made a difference, it really did," lead author Rudolph M. Navari, MD, PhD, from the Indiana University School of Medicine–South Bend, told Medscape Medical News. "The study was strikingly positive and the drug was tolerable and showed no significant side effects.
"In my opinion, this is a practice-changing study," Dr Navari commented. "I expect all of the CINV guidelines (eg, from ASCO [American Society of Clinical Oncology], NCCN [National Comprehensive Cancer Network], MASCC/ESMO [Multinational Association for Supportive Care in Cancer/European Society for Oncology]) to incorporate olanzapine in their recommendations."
The currently used antiemetics — 5-HT3 receptor antagonists, dexamethasone, and the NK-1 receptor antagonists — prevent emesis in 60% to 70% of patients but are not effective in controlling nausea, Dr Navari said. "Olanzapine is the first medication to demonstrate the prevention of nausea post-chemotherapy."
p>Approached for comment, Tracey O'Connor, MD, associate professor in the Department of Medicine at Roswell Park Cancer Institute in Buffalo, New York, said that while strides have been made in managing CINV, "there remains room for improvement, particularly with highly emetogenic chemotherapy regimens."
She noted that olanzapine for CINV is already included in the NCCN guidelines and that dosing and schedules similar to those used in this study have been adopted by "many institutions," including her own. "This study increases our confidence in adding olanzapine when administering highly emetogenic chemotherapy and will likely change practice due to the benefit," she told Medscape Medical News.
The fact that 74% of patients treated with olanzapine in this study experienced no chemotherapy-induced nausea, compared with 45% treated with placebo, "is a remarkable improvement," said Dr O'Connor, who is also assistant professor of medicine and an academic scholar at the Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo.
In the study, 380 patients with malignant disease who had not received previous chemotherapy were randomly assigned to receive the standard prophylactic triple antiemetic therapy plus 10 mg of olanzapine orally or matching placebo daily on days 1 through 4.
The median age for both groups was 57.0 years; 90.3% of patients were white, and 72.4% were female. The primary disease site was the breast in 63.7% and the lung in 12.9%; 23.4% had disease located in another primary site.
All patients received similar doses of cisplatin (≥70 mg/m2) or cyclophosphamide (Cytoxan, Bristol-Myers Squibb)–doxorubicin (Adriamycin, Rubex).
Patients completed daily records of vomiting and the use of rescue therapy for the first 5 days of chemotherapy. They also rated nausea each day on a scale from 0 to 10, with 0 representing "no nausea at all" and 10 indicating "nausea as bad as it can be."
The overall complete response rate — no nausea or vomiting for 5 days — was 63.6% in the olanzapine group compared with 40.6% in the placebo group (P < .001), the study showed.
Patients who received olanzapine were more likely than those who received placebo to be free of clinically significant nausea and vomiting — indicated by a nausea score of less than 3 on a scale from 0 to 10 — in the early, later, and overall assessment periods. This included the first 24 hours after chemotherapy (74% vs 45%; P = .002), the period from 25 to 120 hours after chemotherapy (42% vs 25%; P = .002), and the overall 120-hour period (37% vs 22%; P = .002).
Complete response rate (no emetic episodes and no use of rescue medication) was also significantly increased with olanzapine during the three periods: 86% vs 65% (P < .001), 67% vs 52% (P = .007), and 64% vs 41% (P < .001), respectively.
Although there were no grade 5 toxic effects, 5% of patients receiving olanzapine had increased sedation on day 2, which resolved on days 3, 4, and 5 even though olanzapine was continued. "Patients must be educated about [this] and monitored carefully," Dr O'Connor said.
When these results were presented at a palliative care meeting earlier this year, Mark G. Kris, MD, from the Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York, described them as "amazing" in his Medscape videoblog.
"These are truly amazing results. What is even more amazing is that this drug is sitting in your pharmacy. It literally costs pennies. You could make this change to your care plan today," he commented.
"We seldom have an opportunity to deal with the most critical issue that our patients tell us about. Whenever you ask individuals what they fear most about cancer treatment, it's nausea and emesis. Now we can look them in the eye and say, 'We have a better treatment for that.' " he said.
Already Used Off-Label
Practitioners have been using olanzapine for this off-label purpose "without issues," said Dr Navari, who is also director of the Cancer Care Program for Central and South America for the World Health Organization. He recommends 10 mg/day for 4 days beginning on the day of chemotherapy. "Even if payers do not reimburse, it is very effective and very cheap for patients at $0.45/10 mg (oral)."
Good candidates for the addition of olanzapine during chemotherapy include young women with breast cancer, either in an adjuvant setting after initial diagnosis or those with metastatic disease. "We know that young women who are premenopausal, who do not have any alcohol history but maybe had nausea during pregnancy or have motion sickness, are at high risk for nausea postchemotherapy and would benefit," Dr Navari said.
Individuals who are heavy alcohol drinkers seem to have a much higher threshold for emesis and nausea, he noted. "We're not sure why that is."
Patients receiving multiple days of chemotherapy or chemotherapy before bone marrow transplantation might also benefit from the addition of olanzapine, he suggested.
"We need more research and development on agents to prevent and treat chemotherapy-induced nausea," said Dr Navari. "Future research studies need to use prevention of nausea as the primary endpoint in CINV studies."
The researchers are planning additional studies to see whether olanzapine could replace antiemetic drugs that don't prevent nausea.
Case Study: Use Olanzapine, or Not?
In a case study also reported online July 13 in NEJM Clinical Decisions Interactive, MaryAnn B. Wilbur, MD, MPH, an obstetrician-gynecologist at Beth Israel Deaconess Medical Center in Baltimore, Maryland, asks whether Ms Williams, a 42-year-old woman with a diagnosis of recurrent cervical cancer, might benefit from the new antiemetic regimen.
Should the patient be premedicated with the standard regimen — aprepitant, ondansetron, and dexamethasone? Or should olanzapine be added?
The patient appears to be otherwise healthy and has an unremarkable medical history, except for a tendency toward nausea and vomiting, including motion sickness. She doesn't drink or smoke and is not taking any medication.
The patient had considerable nausea and vomiting with her previous cisplatin-containing therapy and is reluctant to begin treatment again. She wants to know how her side effects will be managed.
In his response, Michael J. Birrer, MD, PhD, from the gynecologic oncology research program at Massachusetts General Hospital in Boston, advocates for standard therapy. He notes that current antiemetic regimens are "reasonably effective" and that in the current study by Dr Navari et al, significant sedation was reported on day 2, as well as a trend toward weight gain.
(Dr Navari responds that olanzapine has been reported to cause weight gain if given daily in higher doses over a period of 3 to 6 months, but this has not been seen when olanzapine is given for 3 to 4 days as an antiemetic.)
"In addition, we need to acknowledge that the long-term consequences of olanzapine and its potential complex interactions with other drugs used in patients with cancer remain undefined," Dr Birrer points out.
Ultimately, he recommends a modified approach, adding olanzapine in the second cycle but only in patients with breakthrough nausea and vomiting. Alternatively, he suggests substituting olanzapine for one of the other antiemetic agents, such as ondansetron. "There are data that support this approach, although more testing would probably be needed to establish the safest and most effective combination," he says.
David R. Spriggs, MD, from the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, advocates for adding olanzapine to the standard regimen. He notes that a 2007 study by Navari et al showed that administration of 10 mg of oral olanzapine for 3 days prevented further emesis in 70% of the patients with severe breakthrough nausea and vomiting.
"Given Ms. Williams's previous negative experiences and her low risk of serious side effects, my preference for this patient would be to add olanzapine to the usual triple antiemetic therapy. This approach seems most likely to minimize the risk of nausea and vomiting while adding little to the overall risk of side effects."
This study was funded by the National Cancer Institute. Disclosure forms are available with the full text of the article at NEJM.org.
N Engl J Med. 2016;375:134-412, 177-179. Abstract Case study
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