Chemotherapy-induced nausea and vomiting (CINV) continues to afflict cancer patients to a great extent.  An estimated 60 to 80% of patients receiving chemotherapy experience some level of nausea and vomiting.¹  The individual risk of developing CINV is dependent upon both patient-related and treatment-related factors.  Patient factors that indicate a higher risk of CINV are female gender, age 50 and under, no alcohol use, susceptibility to motion sickness and prior episodes of CINV.  Treatment-related factors associated with higher rates of CINV include Platinol®-based chemotherapy, combination chemotherapy, higher doses of chemotherapy and high-dose intensity chemotherapy.  For example, the incidence of acute CINV in patients receiving high doses of Platinol® is over 90%.²

The serotonin (5-HT3) antagonists constitute the most effective treatment for CINV thus far and they represent today’s standard of care. These agents are designed to impede one or more of the signals that cause nausea and vomiting.  The administration of certain chemotherapeutic drugs causes a release of serotonin from the enterochromaffin cells of the GI tract.  Serotonin (5-HT3) antagonists work both centrally and peripherally to inhibit the binding of this serotonin to the 5-HT3 receptor, thereby preventing acute nausea and vomiting associated with emetogenic chemotherapy or radiation.  This differs from the pathophysiology associated with chronic nausea, which may involve the stimulation of other receptors.

Acute CINV occurs within the first 24 hours following chemotherapy treatment, with the highest risk period occurring within the first four hours of treatment.³   By definition, delayed CINV occurs more than 24 hours after treatment and may persist for several days.  The results of a multi-national study recently published in Cancer⁴ indicated that physicians and nurses alike underestimated the incidence of delayed nausea and vomiting. The discrepancy between the perceived incidence and the actual incidence may be due in part to the fact that patients often do not report the side effects they experience at home.  In the prospective study, over half of nearly 300 patients receiving highly emetogenic chemotherapy had delayed nausea and vomiting.  Of note, roughly one-third of these patients experienced the delayed nausea and vomiting without prior acute nausea and vomiting. 

Owing to its longer half-life and its higher binding affinity for the 5-HT3 receptor, the newest 5-HT3 antagonist, Aloxi® (palonosetron), maintains a longer duration of action.  Hence, it prevents the nausea and vomiting that occurs during the two to five days following treatment.  Thus far, Aloxi® is the only drug in its class to offer this distinct advantage and it is the first to be approved for the prevention of delayed CINV associated with moderately emetogenic chemotherapy.

Delayed CINV

At the 40th Annual Meeting of the American Society of Clinical Oncologists (ASCO), several investigators elaborated on the prevention of delayed CINV with different 5-HT3 antagonists and explored new agents as well.

Steven M. Grunberg, MD⁵ , and his colleagues questioned whether Aloxi®’s prevention of delayed CINV is truly pharmacologic or simply a carryover effect.  They analyzed the pooled data from two phase III studies comparing Aloxi® to Zofran® (ondansetron) or to Anzemet® (dolasetron) (one study was done in Europe and one in N. America).

In the two identically designed trials, 754 patients received either 0.25 mg Aloxi® or 32 mg Zofran® (study 1) or 100 mg Anzemet® (study 2) as a single IV dose. Data from the two studies were pooled in a way to allow the investigators to compare the Aloxi® arms to the Zofran® or Anzemet® arms.  In addition, the data was examined to compare the incidence of delayed CINV in patients who suffered acute CINV (n=254) from those who did not suffer acute CINV (n=500). Patients without acute CINV were divided into three treatment groups depending upon which anti-emetic agent they were given so that the incidence of delayed CINV could be compared in patients with the same acute experience.

Of the 254 patients who suffered acute CINV, almost twice as many patients treated with Aloxi® were protected from delayed CINV than were patients treated with either Zofran® or Anzemet® (23% vs. 12%).  Of the 500 patients who did not suffer acute CINV, 80% were also protected from delayed CINV if they were taking Aloxi®, whereas 69% were so protected if they were taking one of the other agents.  Due to the greater degree of protection from delayed CINV afforded by Aloxi®, the researchers concluded that this prevention is a direct pharmacologic effect.

Elderly Patients

Interestingly, Swiss investigators, led by Matti Aapro, MD⁶ , utilized data from the same two trials to examine the prevention of delayed CINV in the elderly.  Here, the researchers pooled a subset of 165 patients over age 65 who had received moderately emetic chemotherapy and retrospectively analyzed the efficacy of the three anti-emetic agents.  The chemotherapeutic agents most commonly administered on day one were cyclophosphamide (to 49% of patients), doxorubicin (26%) and Paraplatin® (22%).

During the acute period, between zero and 24 hours post-chemotherapy, 84.8% of Aloxi® patients had a complete response, versus 74.4% of Zofran® or Anzemet® patients. During the delayed period, between 24 and 120 hours after chemotherapy, there was a more significant difference in the complete response rates: 72.2% for Aloxi® patients versus 53.5% for Zofran®/Anzemet® patients.  Furthermore, the proportion of patients with no emetic episodes was higher in the Aloxi® group of patients compared with Zofran®/Anzemet® patients during the acute and delayed periods, but the between-group differences were not statistically significant.  Overall responses are shown below.

*emetic episode

The adverse event profile in this elderly cohort was similar to that observed in the overall population treated with these anti-emetic agents.  The incidences of the most common adverse events were lower in the Aloxi® patients than in the Zofran®/Anzemet® patients (constipation, 9.8% vs. 13.5%; headache, 6.1% vs. 12.4%). Although 30% of these patients had some degree of cardiac impairment, cardiac adverse reactions were infrequent and similar between the two arms, occurring in less than two percent of patients.  The investigators concluded that Aloxi® is not only well tolerated, but it is also more effective than Zofran® or Anzemet® in elderly patients.

Combination Therapy

Combining similar agents to achieve additive chemotherapeutic effects is nothing new to medical oncologists. Hence, it comes as no surprise that researchers are experimenting with different recipes of anti-emetic agents as well.  Emend® (aprepitant) is a substance P/neurokinin 1 (NK1) receptor antagonist approved for the prevention of acute and delayed CINV when used with a 5-HT3 antagonist and dexamethasone.  In the first study to combine Emend® with Aloxi®, Thomas H.Grote,⁷ MD and his colleagues found that the drugs can be safely combined and may improve overall efficacy in patients with moderately to moderate-high emetogenic chemotherapy.

The multi-center, phase II study enrolled 50 patients and Dr. Grote reported the results with the first 39 of them.  Most of the patients were women with breast cancer and the most common regimens were doxorubicin/cyclophosphamide and paclitaxel/Paraplatin®.  Patients received a single IV dose of Aloxi® (0.25 mg) on day 1, along with three daily oral doses of Emend® (125 mg on day 1; 80 mg on days 2-3) plus dexamethasone (12 mg on day 1; 8 mg on days 2-3).  The preliminary results are summarized in the table below.

Zyprexa® (Olanzapine)

Taking a novel approach to tackling delayed CINV, another team found that combining the benzodiazepine, Zyprexa®, with a 5-HT3 antagonist was safe and effective. Rudolph M. Navari,⁸ MD and his co-investigators (in Indiana and Kentucky) based their trial on the observations that psychiatric patients on narcotics do not exhibit the same level of narcotic-induced nausea when they also receive Zyprexa®.  Although benzodiazepines are already employed to treat anxiety in cancer patients, this is the first trial to assess the anti-emetic efficacy of a drug in this class.  It is also the first study to combine a benzodiazepine with a 5-HT3 antagonist.

Using the maximum tolerated dose of Zyprexa®, as determined by a phase I study, this phase II trial was conducted in 30 chemotherapy-naïve patients, more than half of whom had breast cancer. Two days prior to chemotherapy, patients received 5mg/day oral Zyprexa®. On the first day of chemotherapy, they received 10 mg of Zyprexa®, along with intravenous Kytril® (granisetron, 10 mcg/kg), and dexamethasone 20 mg. On days 2-4 after chemotherapy, they received 10 mg/day of Zyprexa® (added to dexamethasone, 8 mg p.o. BID, days 2,3, and 4 mg. p.o. BID, on day 4).

During the acute period, 100% of patients had a complete response (no emesis, no rescue) regardless of the emetogenicity of their treatment.  During the delayed period, 80% of the ten patients who had received highly emetogenic chemotherapy (Platinol® ≥70 mg/m² or Platinol® + doxorubicin) had a complete response, as did 85% of the 20 patients who had received moderately emetogenic chemotherapy (doxorubicin ≥50 mg/m² , or doxorubicin + cyclophosphamide, or irinotecan). Nausea was well controlled in the 10 patients on HEC, with no patient experiencing anything greater than minimal nausea during the acute or delayed period. Nausea was similarly controlled in the 20 patients on MEC, with minimal or no nausea in 85% of patients during the acute period and 70% during the delayed period.

These favorable results were maintained over multiple cycles of chemotherapy; 21 of the 30 patients received at least four cycles.  In addition, Zyprexa® was well tolerated, with no grade 3 or 4 toxicities, and no major severity was noted among a range of 19 symptoms as measured by the M.D. Anderson Symptom Inventory (MDASI).

Pharmacologically, Zyprexa® blocks both 5-HT3 receptors and dopamine receptors in the CNS.  Current anti-emetics work on the periphery, explained Dr. Navari, but they probably do not enter the CNS. Zyprexa® does, hence the additive effect it appears to have when combined with another anti-emetic. 

Comparing Anti-Emetics for Acute CINV

One of the more informative studies presented at ASCO was a meta-analysis comparing the efficacy of several 5-HT3 antagonists for the prevention of acute CINV.  Efficacy was defined as complete acute response with no vomiting and only mild nausea, if any, within the first 24 hours following chemotherapy. German and US investigators, led by Karin Jordan,⁹ MD, retrospectively reviewed 46 studies and conducted subset analyses given the varying study designs, dosing schedules and administration routes.  The studies involved both highly emetogenic chemotherapy (Platinol®-based) and moderately emetogenic treatment (non-Platinol® based). Data with Aloxi® were inadequate to include in the meta-analysis because only one published study compared Zofran® with Aloxi®, and one study compared Anzemet® with Aloxi®.  Hence, the findings focus on Kytril®, tropisetron, Zofran®   and Anzemet®.

With regards to dosing, the fixed effect model meta-analysis indicates a significant result favoring the 24/32 mg dose of Zofran® over the 8 mg dose (p=0.012) suggesting that the smaller dose is suboptimal. There was no significant difference observed between the 1 mg dose and the 3 mg dose of Kytril®.

Analysis of the 12 studies comparing Kytril® to tropisetron, favored Kytril® (p<0.05). Analysis of 11 studies comparing Zofran® to tropisetron indicated a slight advantage of Zofran® following Platinol®-based treatment, and a weak trend favoring tropisetron following non-Platinol®-based treatment.  Yet, a pooling of all Zofran® vs. tropisetron studies showed no significant difference. For the studies comparing Zofran® vs. Anzemet®, there were no differences in the Platinol®-based studies, and an advantage of Zofran® over Anzemet® in only one of two non-Platinol®-studies.

The investigators concluded that the meta-analysis revealed a significant advantage of Kytril® over tropisetron for both highly and moderately emetogenic chemotherapy, but no clear advantage for Zofran® over tropisetron.  They speculated that the apparent inferiority of 8 mg Zofran®, relative to 3 mg Kytril®, amongst the non-Platinol®-based studies, was due to the late onset of acute emesis following moderately emetogenic treatment and to the longer duration of action on the part of Kytril®.

References

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2. Hesketh PJ: Defining the emetogenicity of cancer chemotherapy regimens: relevance to clinical practice. The Oncologist 1999;4:191-6.

3. Gralla R. Management of nausea and vomiting. Cancer Management: A multidisciplinary approach, 2001.

4. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 2004; 100:2261-68.

5. Grunberg SM, Vanden Burgt J, Berry S, et al. Prevention of delayed nausea and vomiting: carryover effect analysis of pooled data from 2 phase III studies of palonosetron. Proc.Am.Soc.Clin.Oncol. 2004; Abstract # 8051.

6. Aapro M, Macciocchi AP, Palonosetron (PALO) is more effective than ondansetron/dolasetron (OND/DOL) in preventing chemotherapy-induced nausea and vomiting (CINV) in elderly patients: Combined results from 2 phase III studies. Proc.Am.Soc.Clin.Oncol. 2004; Abstract #8049.

7. Grote T, Hajdenberg J, Cartmell A, et al. Palonosetron (PALO) plus aprepitant (APREP) and dexamethasone (DEX) for the prevention of chemotherapy-induced nausea and vomiting (CINV) after emetogenic chemotherapy (CT). Proc.Am.Soc.Clin.Oncol. 2004; Abstract #8262.

8. Navari RM, Einhorn LH, Loehrer PJ, et al. A phase II trial of olanzapine for the prevention of chemotherapy induced nausea and vomiting (CINV). Proc.Am.Soc.Clin.Oncol. 2004; Abstract #8046.

9. Jordan K, Hinke A, Grothey A, et al. A meta-analysis comparing the efficacy of five 5-HT-3 receptor antagonists (5-HT3-RAs) for acute chemotherapy-induced emesis. Proc.Am.Soc. Clin.Oncol. 2004; Abstract #8048.