Gallo, MD, L Merlini, MD, C Caroti, MD; Oncologic Center, 'V Fazzi' Hospital, Leece: S Mazzotta, MD, R Forcignano, MD, G Quarta, MD;. Medical Oncology ...
Tumori, 87: 379-382, 2001
IS AN ANTIEMETIC PROPHYLACTIC TREATMENT NEEDED FOR PATIENTS SUBMITTED TO CONSECUTIVE DAYS OF 5-FLUOROURACIL? AN OBSERVATIONAL STUDY The Italian Group for Antiemetic Research*
Aims and Background. The necessity of an antiemetic prophylaxis in patients treated with chemotherapy of low emetogenic potential, such as 5-fluorouracil ± folinic acid fractionated over several consecutive days, is controversial. The aim of the study was to evaluate the therapeutic behavior of oncologists on this issue. Methods. All consecutive in and out patients who started chemotherapy in 33 Italian oncological departments from June 24 to July 6, 1996, were studied. The antiemetic prescription pattern and its effectiveness, in patients submitted to 5-fluorouracil ± folinic acid were evaluated. Results. Of the 1956 patients submitted to cancer chemotherapy, 259 patients received 5-fluorouracil ± folinic acid. Of these, 186 patients were treated for 5 consecutive days, 47 for 4 days, 20 for 3 days and 6 for 2 days. A total of 219 (84.5%) received an antiemetic prophylaxis: 43.4% a 5-HT3 antagonist ± steroids, 37.5% an antidopaminergic drug, 10.9% a steroid ± antidopaminergic drug, and 8.2% other drugs. Only 40 patients (15.5%) did not receive an antiemetic prophylaxis. Overall com-
plete protection from vomiting/nausea was 225/259 (86.9%)/163/259 (62.9%). The complete protection from vomiting/nausea during the 5 days in the 186 patients was not significantly different among patients receiving or not an antiemetic prophylaxis (88.1 %/64.9% vs 88.9%/55.6%). At unifactorial analysis, the previous experience of vomiting/nausea caused by chemotherapy was found to be a significant prognostic factor. In fact, overall complete protection from vomiting/nausea was significantly inferior in patients who had previous experience of vomiting/nausea (65.1%/35.0%) with respect to those who did not (91.20/0175.4%, P < 0.001/ > 0.001, respectively). Conclusions. The study showed that in clinical practice patients submitted to 5-fluorouracil ± folinic acid obtained a similar high protection from vomiting and nausea regardless of whether or not antiemetic prophylaxis was given. It would be therefore reasonable not to treat patients undergoing such chemotherapy, whereas patients with previous experience of vomiting/nausea caused by chemotherapy should be given an antiemetic prophylaxis.
Key words: antiemetics, clinical practice, effectiveness, 5-HT3 antagonists.
Introduction
Chemotherapy regimens containing 5-fluorouracil in combination with folinic acid, administered for several
consecutive days, are widely used in the treatment of cancer patients. The emetogenic potential of these regimens is considered to be low to moderate, but contrasting data are found in the literature 1,2. Moertel et a[.3-6
*Principal investigators: Medical Oncology Service, ASL n. 2, Perugia: Verena De Angelis, MD; Medical Oncology Division, Policlinico Hospital, Perugia: Fausto Roila, MD, Maurizio Tonato MD; Medical Statistics Unit, Dept of Internal Medicine and Public Health, University, L'Aquila: Enzo Ballatori, PhD; Dept of Internal Medicine and Oncological Sciences, University, Perugia, Italy: Albano Del Favero, MD. Investigators and Collaborating centers: Oncologic Center, Aviano: S Tumolo, MD, L Meneghetti, RN, 0 Negri, RN, S Della Gaspera, RN, C Presot, RN, G Muran, RN, A Lucenti, MD; Medical Oncology Division, Perugia: G Ciccarese, MD, MA Palladino, MD, S. Porrozzi, MD; Medical Oncology Opt, University, Modena: R Sabbatini, MD, R Depenni, MD, M Federico, MD, V Silingardi, MD; Medical Oncology Division, ForB: E Sansoni, MD, M Maltoni, MD, C Milandri, MD, 0 Arnadori, MD; Medical Oncology Division, Verona: R Sabbioni, MD, R Nortilli, MD, GL Cetto, MD; Medical Oncology Division, 'S Luigi' Hospital, University, Torino: L Dogliotti, MD, T Buniva, MD, G Gorzegno, MD; Medical Oncology Division, 'Regina Elena' Institute, Roma: M Lopez, MD, A Amodio, MD, F Conti, MD; Medical Oncology Division, 'S Filippo Neri' Hospital, Roma: CM Foggi, MD, A Giglio, MD, L De Sio, MD; Medical Oncology Division, Castelfranco Veneto: P Manente, MD; Medical Oncology Service, Pavia: G Bernardo, MD, MR Strada, MD, G Villani, MD; Medical Oncology Service, Galliera Hospital, Genova: L Gallo, MD, L Merlini, MD, C Caroti, MD; Oncologic Center, 'V Fazzi' Hospital, Leece: S Mazzotta, MD, R Forcignano, MD, G Quarta, MD; Medical Oncology Division, 'Cardarelli' Hospital, Napoli: C Pacilio, MD, G Iodice, MD, G Rosati, MD; Medical Oncology Division, Ferrara: P Malacarne, MD, 0 Donati, MD, R Maccaferri, MD; Medical Oncology, National Cancer Institute, Napoli: G Comella, MD, R Casaretti, MD; Medical Oncology Center, University, Palermo, Palermo: I Carreca, MD, L Rausa, MD; Medical Oncology Division, 'S Bortolo' Hospital, Vicenza: V Fosser, MD, S Schiavon, MD; Surgical Oncology Division, University, Messina: FM Gioffre, MD, A Venuti, MD; Gynecology Institute, 'Careggi' Hospital, Firenze: G Amunni, MD, A Villanucci, MD; Medical Oncology Service, Sassari: A Contu, MD, A Pazzola, MD; Oncology Center, 'Di Venere' Hospital, Bari-Carbonara: G Palmiotti, MD, G Garofolo, MD; Medical Oncology Division, Como: C Epifani, MD, M Giordano, MD; Medical Oncology Center, 'S Eugenio' Hospital, Roma: M Antimi, MD, M Minelli, MD; Medical Oncology Opt, 2nd University, Napoli: F De Vita, MD, G Catalano, MD; Medical Oncology Division, Lugo, Ravenna: G Cruciani, MD, L Montanari, MD; Medical Oncology Oncology Opt, University 'La Sapienza', Roma: P Marchei, MD, S Amici, MD; Medical Oncology Division, Pesaro: P Alessandroni, MD, M Ceccolini, MD; Medical Oncology Division, 'L Sacco' Hospital, Milano: MT Cattaneo, MD, B Orlandini, MD; Medical Oncology Division, 'M Ascoli' Hospital, Palermo: B Agostara, MD; Radiotherapy Oncology Center, Livomo: M Marzi, MD; Dept of Internal Medicine and Oncological Sciences, University, Perugia: MS Dionisi, MD; Medical Oncology Service, 'S Maria' Hospital, Temi: F Di Costanzo, MD; Medical Oncology Division, Bari: G Troccoli, MD. Acknowledgments: The authors thank Glaxo SmithKline S.p.A., Italy, for a grant covering the expenses for printing and distribution of clinical record forms To whom correspondence should be addressed: Fausto Roila, MD, Medical Oncology Division, Policlinico Hospital, 06122 Perugia, Italy. Tel +39-075-5783968; fax +39-075-5720990.
Received April 13,2001; accepted August 22, 2001.
380 found an incidence of 54-80% for nausea and 27-44% for vomiting in patients receiving placebo and submitted to 15 mg/kg/day of 5-fluorouracil for 5 consecutive days. In contrast, the Meta-analysis Group in Cancer? found no differences in nonhematologic toxicities in patients treated with 5-fluorouracil bolus and 5-fluorouracil continuous infusion; the incidence of WHO grade 3-4 nausea/vomiting (emesis requiring an antiemetic therapy or refractory emesis) was 4% and 3%, respectively. Therefore, despite their wide utilization, we do not know whether 5-fluorouracil chemotherapy regimens require a prophylactic treatment and, if so, which would be the treatment of choice. These considerations ~rompted us to conduct an observational study on patients treated with 5-fluorouracil fractionated over several consecutive days to see how these uncertainties are dealt with by oncologists in daily practice. Patients and methods
The data presented herein were collected during an observational drug utilization study on prophylaxis of chemotherapy-induced emesis carried out in Italy". All consecutive in- and out-patients receiving 5-fluorouracil ± folinic acid chemotherapy in 33 Italian oncological centers from June 24 to July 6, 1996, were studied. Excluded from the study were patients receiving concomitant radiotherapy. All patients gave their informed consent to be monitored for nausea and vomiting during 5fluorouracil therapy. The centers were selected on the basis of the following criteria: the homogeneous geographical location of the centers; their statuses as tertiary care institutions; their previous participation in collaborative studies on antiemetics. Prescribers were unaware that their prescriptions were monitored. Patient characteristics, with particular attention to those shown to be important prognostic factors for chemotherapy-induced emesis", as well as type, dose and schedule of antiemetic therapy administered were recorded. Previous experience by participating centers in antiemetic research, defined as at least one participation in an antiemetic trial published in a refereed journal in the last 10 years, was also considered. The effectiveness and tolerability of antiemetic treatment was evaluated by interviewing patients about the presence of nausea, retching, vomiting, use of rescue medications and adverse reactions that occurred during the 24 hrs after the start of cancer chemotherapy. This ~as done by direct or phone interview 24 hrs after beginrung chemotherapy and every day for patients submitted to fractionated chemotherapy in consecutive days. T?e chi-squared test was used to compare two pro~ortlOns. All P values refer to two-tailed tests. Logistic linear models were performed to evaluate the importance of prognostic factors in explaining the variability of the presence of vomiting and nausea.
THE ITALIAN GROUP FOR ANTIEMETIC RESEARCH
Results
Overall, 1,956 patients entered the study and 259 (13.2%) received 5-fluorouracil ± folinic acid for several consecutive days. In particular, 186 patients received the drugs for 5 consecutive days, 47 for 4 days, 20 for 3 days and 6 for 2 days. Patient characteristics known to be important risk factors for chemotherapy-induced emesis are shown in Table 1. They were equally distributed between patients receiving or not receiving an antiemetic prophylaxis. ' Incidence ofnausea and vomiting
Irrespective of prophylactic treatment received, the overall incidence of vomiting was 13% and that of nausea 37%. It is noteworthy that the incidence of emesis was similar in patients irrespective of whether or not they received an antiemetic prophylaxis. Only 40 (18.~%) patients did not receive antiemetic prophylaxis, and m these patients the incidence of vomiting was 5% and that of nausea 27.5%, not dissimilar to that found in patients treated with a variety of antiemetic treatments: 14.6% and 38.8%, respectively (the differences were not significant) (Table 2). The incidence of nausea was always greater than that of vomiting. . The intensity of vomiting/nausea was mild irrespectrve of whether or not the patient received antiemetic
Table 1 - Patient characteristics Total (%)
No. patients receiving an antiemetic prophylaxis (%)
No. patients not recei ving an antiemetic prophylaxis (%)
No. of patients
259
219
40
Age (yr) S; 50 50-64 ?: 65
43 (16.6) 124 (47.9) 92 (35.5)
37 (16.9) 101 (46.2) 81 (36.9)
6 (15.0) 23 (57.5) II (27.5)
Sex male female
135 (52.1) 124 (47.9)
113 (51.6) 106 (48.4)
22 (55.0) 18 (45.0)
Alcohol intake! none or low moderate-high
172 (66.9) 85 (33.1)
149 (68.0) 70 (32.0)
23 (57.5) 17 (42.5)
Kinetosis (*) no yes
234 (91.1) 23 (8.9)
195 (89.9) 22(10.1)
39 (97.5) 1(2.5)
Performance status 80-100 < 80
202 (78.0) 57 (22.0)
169 (77.2) 50 (22.8)
33 (82.5) 7 (17.5)
Previous CT-induced nausea no 179 (69.1) yes 80 (30.9)
149 (68.0) 70 (32.0)
30 (75.0) 10 (25.0)
Previous CT-induced vomiting no 216 (83.4) yes 43 (16.6)
179 (82.0) 40 (18.0)
37 (92.5) 3 (7.5)
Type of patients untreated pretreated
25 (11.4) 194 (88.6)
5 (12.5) 35 (87.5)
I
30 (11.6) 229 (88.4)
Data for 2 patients were not reported.
ANTIEMETIC PROPHYLACTIC TREATMENT NEEDED FOR PATIENTS SUBMITTED TO CONSECUTIVE DAYS OF 5-FU
Table 2 - Incidence of nausea/vomiting according to antiemetic prophylaxis Antiemetics
No.
5-HT3 antagonist + steroids 5-HT3 antagonist ± other Steroids Metoclopramide Alizapride Steroids + antidopaminergic Other No antiemetic prophylaxis Overall antiemetic prophylaxis Overall
86 12 22 60 12 18 40 219 259
9
Incidence of vomiting
Incidence of nausea
22.2 16.3 8.3 27.3 10.0 8.3 11.1 5.0 14.6 13.1
44.5 45.3 16.7 40.9 36.7 16.7 38.9 27.5 38.8 37.1
therapy. Of the group who received the therapy (n = 259), vomiting/nausea was reported by 7.2%/9.3% of patients for only 1 of 5 days, by 1.2%/10.1% of patients for 2 of 5 days, by 3.8%/8.1 % for 3 of 5 days, by 0.9%/4.6% for 4 of 5 days, and by 0%/5% of patients for 5 of 5 days. The distribution rates of complete protection among patients according to the antiemetic drug prescribed for prophylaxis did not shown any significant difference. Using logistic linear models, the only important prognostic factor for response to therapy was previous experience of vomiting and nausea. In fact, in patients who did not suffer from vomiting/nausea during previous chemotherapy, complete protection from vomiting/nausea (91.2%/75.4%) was significantly better than in patients who previously had vomiting/nausea (65.1%/35.0%) (P < O.OOOlfP < 0.0001) (data not shown). Prescription pattern ofantiemetic prophylaxis
Of the 85% of patients submitted to an antiemetic prophylaxis, about 37% received a 5-HT3 receptor antagonist, whereas a benzamide derivative, especially alizapride, was used in about 30-35% of patients. It is noteworthy that the prescription of a particular class of antiemetics, or the choice of not treating the patient, was not significantly related to any of the already known prognostic factors, such as previous experience of nausea and vomiting induced by chemotherapy, sex, age or alcohol intake. Discussion
Scanty and contrasting data exist regarding whether to recommend a prophylactic treatment of nausea and
381
vomiting induced by widely used regimens of chemotherapy with 5-fluorouracil ± folinic acid administered for consecutive days. Furthermore, no data are available on how this problem is dealt with by oncologists in their daily clinical practice. The present study clearly showed that despite the lack of convincing evidence, most oncologists participating in the study prescribed in their daily practice a wide range of antiemetic prophylactic treatments to patients receiving 5-fluorouracil ± folinic acid chemotherapy. In the study, an antiemetic was prescribed in approximately 85% of patients, and the drug was a 5-HT3 receptor antagonist in about 40% of cases. However, the usefulness of such prophylaxis is highly questionable. In fact, the incidence of vomiting/nausea in patients not receiving any form of prophylaxis was found to be very low (5/27.5%), not different from that found in patients receiving prophylaxis (14.6/38.8%). However, these results must be viewed with caution. In fact, the number of patients not receiving prophylaxis was small (18.3% of all patients), and the study was not a randomized clinical trial. Moreover, a selection bias when the oncologist decides which patients should be treated (or not be treated) on the basis of the presence of some risk factors cannot be excluded, although such a bias seems unlikely in our study as the prescription was unrelated to any of the prognostic factors listed in Table 1. A clinically important finding of the study was the clear, statistically significant inferior complete protection from vomiting and nausea achieved by the antiemetic prophylaxis in patients who did not suffer from vomiting and nausea during previous cancer chemotherapy. This prognostic factor, well known for many other types of emetogenic cancer chemotherapy, must be taken into account by the oncologist even in patients receiving a low emetogenic drug such as 5-fluorouracil. However, the study may suggest a clear trend toward over-prescribing antiemetic prophylaxis in these patients irrespective of the presence of any important risk factor of emesis. More studies are needed to clarify which patients receiving 5-fluorouracil chemotherapy require an antiemetic prophylaxis and the optimal antiemetic regimen. At present, it appears that only the unfavorable prognostic subgroup of patients with previous experience of vomiting and nausea probably requires an antiemetic treatment.
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THE ITALIAN GROUP FOR ANTIEMETIC RESEARCH
clinical .practice of the results of controlled clinical trials: the case of antiemetic prophylactic treatment for cancer chemotherapy-induced nausea and vomiting. Ann Oncol, 9: 759-765, 1998. 9. Tonato M, Roila F, De Favero A: Methodology of antiemetic trials: a review. Ann Oncol, 2: 107-114, 1991.
