Central nervous system side-effects of 5-HT3-receptor antagonists in elderly cancer patients treated with chemotherapy

P. Tralongo*,1, A. Dimari1, G. Conti1, R. Aiello2 and G. Mauceri1

1 G. Di Maria Hospital, Medical Oncology, Avola, Siracusa; 2 Centro Catanese di Oncologia, Medical Oncology, Catania, Italy

*E-mail: tralongo.paolo@virgilio.it

The side-effect profile of supportive treatment is particularly important in the subgroup of elderly patients, as they are susceptible to adverse effects. Such patients may be suffering co-morbidity conditions, taking multiple medications and therefore may be unable to tolerate any further reduction to their quality of life.

Nausea and vomiting are typical side-effects of chemotherapy and also occur in a significant number of patients who are undergoing radiation therapy or surgery. The 5-HT3-receptor antagonists are used for prophylaxis against chemo- and radiotherapy induced emesis. A recent meta-analysis identified 14 randomised, controlled trials directly comparing ondansetron and granisetron; the two agents showed equivalent efficacy in the control of acute-onset and delayed-onset vomiting and nausea after either highly emetogenic or moderately emetogenic chemotherapy [1]. Their administration is usually well tolerated and associated with few side-effects. However, central nervous system (CNS) effects, such as headaches, dizziness and abnormal vision, are complications of 5-HT3 receptor antagonist treatments. Dizziness and light-headedness were reported to occur in between 11% and 21% of chemotherapy patients administered ondansetron [2]. More patients who received ondansetron reported dizziness and abnormal vision than those patients that had received granisetron [34]. In 623 patients receiving moderately emetogenic chemotherapy for breast cancer, a ondansetron infusion at a dose of 32 mg produced abnormal vision in significantly more patients than granisetron administered by mouth at a dose of 2 mg (6.28% versus 0.35%, respectively; P = 0.001) [2]. The reason for these differences may be due to the different pharmacokinetic properties [5, 6]. However, to date, no data on the CNS effect of ondansetron at a lower dose has been published.

We randomly selected 58 patients, aged ≥70 years (mean, 74 years), being treated with moderately emetogenic chemotherapy, to receive a treatment of granisetron 3 mg (5 min infusion) or ondansetron 16 mg (15 min infusion), 30 min before chemotherapy. All patients received the same antiemetic for 2 days following treatment; granisetron was administered by mouth at a dose of 2 mg, whilst ondansetron was administered at a dose of 8 mg sublingually. Patients were randomised 1:1, stratified according to centre. All the patients gave their oral consent. The study had the approval of the Bioethical Committee of our hospital. The most frequent chemotherapy consisted of intravenous (i.v.) cyclophosphamide 600 mg/m2, carboplatin at a dose of ≥300 mg/m2, epidoxorubicin 70 mg/m2. The chemotherapy was well balanced in both groups. Of the patients treated with ondansetron, 11 were undergoing therapy with carboplatin, nine with epidoxorubicin, three with epidoxorubicin plus cyclophosphamide; and of the patients treated with granisetron, 14 were undergoing treatment with carboplatin, 11 with epidoxorubicin and four with epidoxorubicin plus cyclophosphamide.

On the day of the outpatient appointments, before chemotherapy treatment, the patients completed a series of clinically administered measures (diagnostic interview for CNS symptoms, Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) questionnaires); medical records were reviewed to obtain information on the type of cancer, type of chemotherapy and co-morbidity; a physical examination was performed and all medications taken within the previous 2 weeks were also recorded. Twelve patients took drugs (diclofenac, rabeprazole, pravastain) with potential CNS side-effects, of which seven were in the ondansetron treatment group. However, none of these patients showed CNS symptoms at the time of entering the study. Both 2 and 7 days later, patients were contacted by telephone and interviewed about treatment side-effects. Two different oncologists conducted study interviews; the first one interviewed the patient at basal level, whilst the second administered the re-evaluation. A total of 57 patients were evaluated of whom 29 and 28 patients were randomly selected to receive granisetron ondansetron, respectively. One of the patients withdrew from the study because of an early brain progression. Forty-eight (68.5%) patients received dexamethasone 8 mg e.v., before chemotherapy treatment; 21 of them were treated with granisetron.

Of the 22 patients who reported CNS symptoms, 10 (34.48%) received granisetron and 12 (42.85%) ondansetron; the difference in incidences reported was not statistically significant (P = 0.592). Headache was the most frequently reported side-effect (52.7%) and was reported in 24.1% of patients who had received granistron and in 28.6% of those that had received ondansetron. Dizziness and abnormal vision were reported for both granisetron (6.9% and 3.4%, respectively) and ondansetron (14.35% and 7.1%, respectively). The differences of incidence were not statistically significant for headaches (P = 0.770) and abnormal vision (P = 0.611), while a marginal statistically significant difference was registered for dizziness (P = 0.423) (Table 1). All the CNS symptoms reported were mild, of brief duration and, most importantly, no difference in the ADL/IADL questionnaires was registered. However, the statistical limitations of this study do not allow us to conclude whether the observed increased frequency of CNS side-effects with ondansetron is significant or not.


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Table 1. Frequency of symptoms
 

REFERENCES

1. Del Giglio A, Soares HP, Caparroz C et al. Granisetron is equivalent to ondansetron for prophylaxis of chemotherapy-induced nausea and vomit. Results of a meta-analysis of randomised controlled trials. Cancer 2000; 89: 2301–2308.[CrossRef][ISI][Medline]

2. Grunberg SM. Phase I and other dose-ranging studies of granisetron. Semin Oncol 1992; 19 (Suppl 10): 16–22.

3. Perez EA, Hesketh P, Sandbach J et al. Comparison of single-dose oral granisetron versus intravenous ondansetron in the prevention of nausea and vomiting induced by moderately emetogenic chemotherapy: a multicentric, double-blind, randomised parallel study. J Clin Oncol 1998; 16: 754–760.[Abstract]

4. Perez EA, Lembersky B, Kaywin P et al. Comparable safety and antiemetic efficacy of a brief (30-sec bolus) intravenous granisetron infusion and standard (15-min) intravenous ondansetron infusion in breast cancer patients receiving moderately chemotherapy. Cancer J Sci Am 1998; 4: 52–58.[Medline]

5. Blower P. A pharmacological profile of oral granisetron (Kytril tablets). Semin Oncol 1995; 4 (Suppl 10): 3–5.

6. Tyers MB, Bunce KT, Humphrey PP. Pharmacological and anti-emetic properties of ondansetron. Eur J Cancer Clin Oncol 1989; 25 (Suppl 1): S15–S19.[ISI][Medline]





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