A combination of 5-hydroxytryptamine and dexamethasone is recommended for the prevention of cisplatin-induced emesis. 1 Although patients with cancer typically undergo multiple cycles of chemotherapy, studies investigating the persistence of antiemetic efficacy over consecutive cycles are scarce, 2–6 with this efficacy appearing to decrease for subsequent cycles of chemotherapy. 2–7 Because the causes of this attenuation of efficacy are unknown, we believe that it is important to identify the factors for reducing the maintenance of complete and persistent protection from both vomiting and nausea.
Women had a significantly higher rate of chemotherapy-induced emesis. 4,6,7 We observed from a crossover antiemetic study that gender was the important predicting factor for reducing the maintenance of complete protection from emesis during chemotherapy cycles.
PATIENTS AND METHODS
Patients
All patients in this study were scheduled to receive a minimum dose of 50 mg/m2 of cisplatin, followed by continuous infusion of 5-fluorouracil, with or without other chemotherapy agents. Cisplatin was administered on day 1 and the other drugs on day 1 and the subsequent days (Table 1). Eligibility criteria were: age 16 years or more, no prior exposure to cisplatin-containing chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0 to 2. All patients were hospitalized during chemotherapy administration. The study was approved by the hospital ethics committee.
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TABLE 1: Characteristics of patients
Antiemetic Therapy
This was a single-institution study using a crossover design. The same chemotherapy drug was used for both of the principal treatments, at identical doses. Before the first cycle of chemotherapy, patients were assigned to one of two antiemetic treatment groups according to their registration number (odd or even number). Treatment protocols were then alternated for each patient for the second cycle of chemotherapy.
Arm A
All odd-numbered registrations received Arm A for the first cycle. Each chemotherapy cycle consisted of cisplatin 50 to 100 mg/m2, dexamethasone 20 mg, and 20% mannitol 100 to 150 ml, administered in 500 ml 5% dextrose in normal saline for 3 hours. Ondansetron (Zofran; Glaxo Wellcome Inc., Victoria, Australia), 8 mg in 100 ml dextrose, was given as a 15-minute intravenous infusion starting 30 minutes before cisplatin administration, followed by ondansetron intravenous infusion every 4 hours for a total of three doses. In addition, all patients received 5 mg intravenous dexamethasone every 12 hours after the cisplatin administration, with the drug discontinued after completion of the chemotherapy cycle.
Arm B
All even-numbered registrations received Arm B for the first chemotherapy cycle. Ondansetron 8 mg was given as a 15-minute intravenous infusion, beginning 30 minutes before cisplatin treatment, followed by ondansetron intravenous infusion, at 24 and 48 hours after cisplatin administration, for a total of three doses. Dexamethasone was given as in Arm A.
Arm C
Where complete protection from nausea and vomiting was maintained for both principal treatment protocols, Arm C, a single dose of ondansetron 8 mg, 30 minutes before administration of cisplatin, was administered for cost savings. Guidelines of the American Society of Clinical Oncology recommended that single doses of serotonin receptor antagonists are effective and are preferred for convenience and cost. 1 Dexamethasone was given as in the other treatments. Where protection from nausea and vomiting did not persist using this cost-effective alternative, Arm A was substituted for Arm C for the subsequent cycles of chemotherapy.
Response Assessment and Statistical Methods
Data concerning vomiting and nausea were recorded daily by the investigators beginning on admission, and continued after discharge with patients asked to record their own symptoms. Efficacy of antiemetic therapy was defined as follows: complete response (0 episodes); major response (1–2), minor response (3–5), and failure (>5). Severity of nausea was rated by the patient as none, mild, moderate, and severe. Statistical analysis of vomiting and nausea data was performed separately for day 1 (acute episodes), and days 2 to 6 (delayed episodes). The chi-square test was used to compare the relative efficacies of the two antiemetic treatments, and vomiting and nausea, for the first, second, and subsequent cycles of chemotherapy. A p value less than 0.05 was considered statistically significant.
RESULTS
A total of 413 patients were enrolled from December 1995 through July 2000, at Chang-Gung Memorial Hospital. Of these, 400 patients were eligible for emesis during the first cycle of chemotherapy. The population consisted of 256 men and 144 women, ranging in age from 16 to 80 years (median = 57). During the second cycle of chemotherapy, 321 patients continued the evaluation for emesis. There were 363 patients in Arm A and 358 patients in Arm B. Patient’s characteristics are listed in Table 1.
Efficacy and Adverse Events
Antiemetic efficacy data for Arm A and B, for the first cycle of chemotherapy, are listed in Tables 2 and 3. Complete protection rates for both vomiting/nausea through days 1 to 6 were 69.7%/58.4% for Arm A and 71.2%/60.9% for Arm B, and 69.0%/60.0% in first cycle of chemotherapy, respectively. There were no significant differences in the control of either acute or delayed vomiting and nausea between two arms in this study.
TABLE 2: Emetic response (vomiting and nausea)
TABLE 3: Correlation of antiemetic efficacy with patient characteristics during first cycle of chemotherapy
Adverse events tended to be minor, with constipation and hiccups most common, occurring for 23.7% and 23.4% of Arm A, and 23.7% and 22.6% of Arm B, respectively. Dizziness, flushing, headache, and diarrhea were other adverse effects.
Relationship of Clinical Factors and Emesis
Comparisons for vomiting and nausea data and patient characteristics for the first chemotherapy cycle are presented in Table 3. The complete control rate for vomiting and nausea was significantly lower for female patients for days 1 to 6 (p < 0.0001 and p = 0.0005, respectively), and high cisplatin dosage (p = 0.0003 and <0.0019, respectively).
Where complete protection from both vomiting and nausea was achieved during previous cycles of chemotherapy, patients were included for antiemetic study in subsequent cycles (Table 4). The complete control of vomiting/nausea through days 1 to 6 was maintained for 91.4%/86.6% of patients during the second cycle, and for 81.5%/71.1% of patients during the third through sixth cycles, with rates of 91.1%/85.2%, 93.9%/89.9%, 94.7%/92.6%, and 94.9%/94.9%, respectively. Associations for maintenance of complete protection from emesis and patient characteristics are listed in Table 5. Rates for complete and sustained protection from vomiting and nausea were significantly lower for female patients (p = 0.048 and p = 0.0004 during the second cycle, and p = 0.0006 and p = 0.0008 during the third through sixth cycles, respectively).
TABLE 4: Maintenance of complete control rates of vomiting and nausea in patients who had not had emesis during the previous cycles
TABLE 5: Correlation of maintenance of complete control from emesis with patients characteristics during second cycle of chemotherapy
DISCUSSION
Numerous factors may influence control of nausea and vomiting. Important predicting factors include gender, age, history of alcohol intake, the setting for administration of antineoplastic agents, and dosage of cisplatin. 1,4,8–10 The complete control rate for vomiting and nausea in our study, through days 1 to 6 of the first cycle of chemotherapy, was significantly lower for female patients and high-dose cisplatin treatment.
During consecutive cycles, the number of patients decreased as a consequence of disease progression, death, loss to follow-up, side effects of the chemotherapy, and modification of the anticancer treatment. A higher antiemetic efficacy was demonstrated for the ondansetron combination in comparison to a metoclopramide combination during repeated courses of chemotherapy. 2,4,7 With ondansetron plus dexamethasone treatment, complete protection rates for acute nausea, and both vomiting and nausea decreased during subsequent cycles. 3,4,7 The maintenance rates of complete protection from acute vomiting and nausea during chemotherapy cycles were approximately 95% of our patients.
Dexamethasone alone may provide adequate protection against delayed emesis for patients who have not had the acute form. 10 We gave dexamethasone alone for the prevention of delayed emesis during the third through sixth cycles of chemotherapy. For those who have not had acute and delayed emesis during the previous cycles, complete control rates for vomiting/nausea were maintained at greater than 90%/85% during the third through sixth cycles of therapy, respectively. These results are comparable to the 87.4% for complete control of both delayed vomiting and moderate-to-severe nausea reported in 2000 by the Italian Group for Antiemetic Research. 10
Gender and age are two important prognostic factors that may influence antiemetic efficacy during each cycle of chemotherapy. 4 For approximately 10% of our patients, complete protection from vomiting and nausea could not be maintained for each treatment cycle. Gender is the most significant prognostic factor, with maintenance of complete protection from vomiting and nausea significantly reduced for female patients during the second cycle, and during the third through sixth cycles.
In conclusion, the results suggest that women had less maintenance for complete protection from both vomiting and nausea during chemotherapy cycles.
REFERENCES
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