Introduction

Chemotherapy-induced nausea and vomiting (CINV) is a feared side effect of chemotherapy that adversely affects important quality-of-life parameters, including the ability to perform routine tasks and functions and to enjoy leisure time with friends and family. 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 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.

Aloxi ® (palonosetron) is a long-acting, second-generation 5-HT3 receptor antagonist that was recently approved by the U.S. Food and Drug Administration (FDA) for the prevention of acute CINV in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). It was also approved for the prevention of delayed CINV in patients receiving MEC.

Owing to its longer half-life and its higher binding affinity for the 5-HT3 receptor, Aloxi® 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.

The results of three studies were presented at the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology symposium in Miami, Florida (June 2004) that summarized clinical trial results evaluating Aloxi®. The results of these studies are summarized below.

Improved Control of CINV and Quality of Life

In order to assess the impact of improved control of CINV on various quality-of-life parameters, researchers performed a subset analysis of results from two large phase III clinical trials (99-03 and 99-04) that were designed to compare single-dose Aloxi® with single-dose Zofran® (ondansetron) and single-dose Anzemet® (dolasetron).³ The pooled cohort from these two trials included 754 patients, half of whom received single-dose Aloxi® and the other half of whom received either single-dose Zofran® or single-dose Anzemet® 30 minutes prior to the administration of chemotherapy. Baseline demographics were similar among the groups.

Functional Living Index-Emesis (FLIE) scores were generated from patient self-assessment questionnaires about the impact of CINV on daily activities. The FLIE scores were then compared for patients who received Aloxi® and those who received Zofran® or Anzemet®. Patient responses regarding the effect of CINV on daily activities were recorded on day 2 (to reflect the acute impact on day 1) and day 5 (to reflect the delayed impact on days 2-4). The researchers hypothesized that optimal antiemetic therapy should eliminate any impact of CINV on daily life; therefore, the FLIE endpoint that was assessed was “minimal or no impact of CINV on daily life” (NIDL).

The FLIE scores indicated that significantly more patients who were treated with Aloxi® reported NIDL than those who were treated with Zofran® or Anzemet®. This was true for both the acute and delayed phases of CINV. See Table 1 below for the results of this analysis.

Table 1: Percent of Patients Reporting NIDL for Nausea, Vomiting, and Nausea/Vomiting

The researchers concluded that a significantly greater number of patients treated with Aloxi® experienced NIDL during both the acute and delayed periods after MEC than did patients who were treated with Zofran® or Anzemet®. Furthermore, they noted that there was a clear correlation in patients treated with Aloxi®, with complete response (CR) correlating with CINV having no effect on daily living. From these results, the researchers asserted that the superior anti-emetic effect of Aloxi® over Zofran® and Anzemet® allowed more patients to perform daily functions for multiple days after MEC.

The Relationship Between Body Weight and Efficacy of Aloxi®

In order to assess the potential impact of body weight on response to Aloxi® injection, researchers performed a subset assessment from pooled data from two large phase III clinical trials (99-03 and 99-04) as mentioned above.⁴ Again, the pooled cohort included 754 patients, 378 of whom were treated with Aloxi® and 376 of whom were treated with either Zofran® or Anzemet®. Of the patients treated with Aloxi®, a subset of 41 patients weighed more than 90 kg.

To assess whether efficacy was impacted by body weight, acute, delayed and overall complete response (CR) rates were calculated for the subset of patients who weighed more than 90 kg and then compared to the overall population in the study. (Complete response was defined as no emetic episodes and no rescue therapy.) Response rates in the >90 kg subset indicated that there was no diminished efficacy of Aloxi® injection in these patients. In fact, the results of the comparison indicated that responses in the >90 kg subset were comparable to or higher than the responses in the overall pooled study population treated with Aloxi® injection. Furthermore, in the pooled overall population, a single, fixed dose of Aloxi® was more effective than Zofran® or Anzemet® in the prevention of acute and delayed CINV. (See Table 2 below.)

Data from the pooled overall study group demonstrated that a fixed single dose of Aloxi® is more efficacious in CINV prevention during the 5-day post-chemotherapy period than Zofran® or Anzemet® and that Aloxi®-treated patients weighing more than 90 kg do not experience decreased efficacy.

Safety of Repeated Dosing with Aloxi®

Aloxi® has been shown to be effective against acute and delayed CINV when administered as a single, fixed dose prior to emetogenic chemotherapy; however, some emetogenic chemotherapy agents are administered daily for several consecutive days. Therefore, researchers conducted a double-blind, randomized, placebo-controlled study to evaluate the pharmacokinetics and safety of repeat doses of Aloxi® injection.⁵

The study included 16 healthy male and female subjects who received either a single dose of Aloxi® or placebo administered on three consecutive days. Serial plasma samples were collected prior to drug administration and at 11 other points during the 24 hours following drug administration on days one and three and as a single sample on days 5, 7, 8 and 10. Safety was assessed by clinical evaluation of adverse events (AEs), physical examination, electrocardiogram, vital signs, and laboratory testing.

The investigators presented the following pharmacokinetics data for the 12 subjects (6 males and 6 females) who received a single daily IV dose of Aloxi® on 3 consecutive days:

• On day 1, mean Cmax was 1130 ng/L; AUC0-24 was 8900 ng∙hr/L.
• On day 3, mean Cmax was 2430 ng/L; AUC0-24 was 18,200 ng∙hr/L.
• Mean plasma elimination half-life of PALO was 42.8 hours.
• AUC0-24 on day 3, compared with that on day 1, showed a mean accumulation ratio of 2.1, a finding consistent with the long half-life of Aloxi®.

A summary of all treatment emergent AEs showed that 6 of the 12 Aloxi®-treated subjects reported 11 AEs and 2 of the 4 placebo-treated subjects reported 2 AEs. AEs in the Aloxi®-treated group included headache (2), dysmenorrhea (2), migraine (1), musculoskeletal chest pain (1), cough (1), pharyngitis (1), contact dermatitis (1), dry skin (1), and pruritus (1). One case each of contact dermatitis and injection site paresthesia was reported in the placebo-treated group. With the exception of 2 AEs (1 headache and 1 migraine) that were evaluated as “moderate,” all other AEs were deemed “mild.” Only pruritus was considered “possibly related to study drug.” No clinically significant changes were noted in laboratory values or vital signs or on electrocardiogram.

The investigators concluded that daily administration of Aloxi® on 3 consecutive days was well tolerated and that the degree of Aloxi® accumulation in plasma was predictable, given the long elimination half-life of the drug. Data showed that plasma Aloxi® concentration decreased biphasically (a rapid distribution phase was followed by a slower elimination phase) and was measurable for as long as 168 hours after dose administration on day 3. Furthermore, the safety profile of Aloxi® was similar to that found in previous clinical studies of healthy subjects, and exposure did not exceed that of a single 0.75-mg dose, which was well tolerated in previous studies.

References

1. Berger A, Clark-Snow RA. Nausea and Vomiting. In: DeVita VT, Rosenberg SA, Hellman S, eds. Cancer: Principles and Practice of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins, 1997:2705-12.

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

3. Cunningham R, Eisenberg P, Johnson J, et al. Palonosetron (PALO) Is More Effective Than Ondansetron or Dolasetron (OND/DOL) in Reducing the Impact of Chemotherapy-Induced Nausea and Vomiting (CINV) on Daily Life Activities. Proceedings of MASCC/ISOO 16th International Symposium Supportive Care in Cancer. Miami Beach. June 26, 2004.

4. Rubenstein E and Macciocchi A. The Efficacy of a Single Fixed 0.25-mg Intravenous (IV) Dose of Palonosetron (PALO) in Preventing Acute and Delayed Chemotherapy- Induced Nausea and Vomiting (CINV) Is Not Affected by Body Weight. Proceedings of MASCC/ISOO 16th International Symposium Supportive Care in Cancer. Miami Beach. June 26, 2004.

5. Hunt T, Shut A, Gallagher S. Repeated daily intravenous (IV) dosing of palonosetron (PALO), a novel 5HT3 receptor antagonist, is safe and shows predictable pharmacokinetics (PK). Proceedings of MASCC/ISOO 16th International Symposium Supportive Care in Cancer. Miami Beach. June 26, 2004.