Background. To test two different antiemetic regimens for preventing nausea and vomiting in patients with non-Hodgkin's lymphoma (NHL) undergoing systemic chemotherapy (CT) with ProMECE-CytaBOM (P-C). Patients and Methods. Twenty consecutive untreated adult outpatients with histologically confirmed NHL and scheduled to receive P-C chemotherapy were registered in a randomized, double-blind, cross-over study to compare the antiemetic efficacy of a levosulpiride (LS)-based and metoclopramide (MTC)-based regimen. Results. Complete protection from vomiting was recorded in 93% (62/67) of courses with the LS-regimen and in 89% (62/70) with the MTC-regimen (p = 0.428). No nausea was observed in 84% (56/67) of courses with the LS-regimen and in 74% (52/70) with the MTC-regimen (p = 0.183). No differences in prevention of emesis were recorded when patients crossed to the other regimen. Both regimens were well tolerated; however, on day 8 of chemotherapy, when both antiemetic regimens were administered at a higher dose, the LS-based combination showed significantly lower toxicity (p = 0.035). Conclusions. ProMECE-CytaBOM-induced emesis can be prevented in most cases with appropriate, specifically designed antiemetic therapy. Both the LS- and MTC-based combinations resulted in a high percentage of complete protection from emesis, but the higher incidence of side effects observed with MTC makes the LS-based regimen preferable for patients receiving P-C chemotherapy

Baldini, L

Barbieri, F

Federico, Massimo

Maiolo, Mt

Sabbatini, R

Silingardi, Vittorio

SABBATINI R

BALDINI L

BARBIERI F

MAIOLO MT

FEDERICO, Massimo

SILINGARDI, Vittorio

Archivio istituzionale della ricerca - Università di Modena e Reggio Emilia

Correspondence: Dr. Massimo Federico, Oncologia Medica, Policlinico, via del Pozzo 71, 41100 Modena, ItalyAcknowledgments: this work was supported in part by grants from the MURST and the Associazione Italiana per la Ricerca sul Cancro, Milano.Received May 5, 1995; accepted July 25, 1995.original paperHaematologica 1995; 80:416-420ABSTRACTBackground. To test two different antiemetic regimens for preventing nausea and vomiting inpatients with non-Hodgkin’s lymphoma (NHL) undergoing systemic chemotherapy (CT) withProMECE-CytaBOM (P-C).Patients and Methods. Twenty consecutive untreated adult outpatients with histologically con-firmed NHL and scheduled to receive P-C chemotherapy were registered in a randomized, double-blind, cross-over study to compare the antiemetic efficacy of a levosulpiride (LS)-based and metoclo-pramide (MTC)-based regimen. Results. Complete protection from vomiting was recorded in 93% (62/67) of courses with the LS-reg-imen and in 89% (62/70) with the MTC-regimen (p = 0.428). No nausea was observed in 84% (56/67)of courses with the LS-regimen and in 74% (52/70) with the MTC-regimen (p = 0.183). No differencesin prevention of emesis were recorded when patients crossed to the other regimen. Both regimenswere well tolerated; however, on day 8 of chemotherapy, when both antiemetic regimens were admin-istered at a higher dose, the LS-based combination showed significantly lower  toxicity (p = 0.035). Conclusions. ProMECE-CytaBOM-induced emesis can be prevented in most cases with appropriate,specifically designed antiemetic therapy. Both the LS- and MTC-based combinations resulted in a highpercentage of complete protection from emesis. However, the higher incidence of side effects observedwith MTC makes the LS-based regimen preferable for patients receiving P-C chemotherapy.Key words: emesis, levosulpiride, metoclopramide, non-Hodgkin’s lymphoma, ProMECE-CytaBOMThe combination of prednisone, doxoru-bicin, cyclophosphamide, and etoposidefollowed by cytarabine, bleomycin, vin-cristine, and methotrexate with leucovorin res-cue (ProMACE-CytaBOM, P-C)1 represents ahighly effective treatment for patients with ag-gressive, non-Hodgkin’s lymphomas.2-5However, P-C chemotherapy (CT) is associat-ed with several, sometimes dose-limiting side-effects, including myelosuppression, alopecia,mucositis, peripheral neurotoxicity, cardiotoxici-ty, and emesis. The emetogenic potential of P-C is mostly dueto doxorubicin and cyclophosphamide on day 1,and the association of cytarabine, vincristine,bleomycin and methotrexate on day 8 of eachcycle. On the whole, P-C is regarded as a moder-ately emetogenic chemotherapeutic program,and patients treated with this regimen should  beadequately protected against nausea and vomit-ing. To date, little information is available on theefficacy of antiemetic medications for patientsreceiving P-C. In a recently published report bythe GISL (Gruppo Italiano per lo Studio deiLinfomi) on a series of patients treated with P-C,standard antiemetic protection with metoclo-pramide (MTC) (Plasil, Lepetit S.p.A., Milano)and promethazine proved ineffective in overA RANDOMIZED, DOUBLE-BLIND, CROSS-OVER STUDY COMPARING ALEVOSULPIRIDE-BASED AND A METOCLOPRAMIDE-BASED COMBINA-TION IN THE PREVENTION OF PROMECE-CYTABOM-INDUCED EMESISRoberto Sabbatini*, Massimo Federico*, Luca Baldini°, Fausto Barbieri*, Maria Teresa Maiolo°,Vittorio Silingardi**Medical Oncology, Department of Medical, Oncological and Radiological Sciences, University of Modena; °G. Marcora Center,Hematology Service, University of Milan, Italy41750% of cases, especially against drugs deliveredon day 8.5Levosulpiride (LS) (Levopraid, Ravizza Far-maceutici S.p.A., Milano) is a benzamide com-pound with a selective dopamine (D2) receptorantagonist that has been seen to be highly effec-tive in the prevention of CT-induced emesis.6Moreover, compared to MTC, this sulpiridestereoisomer seems to present a lower toxicityrate with no extrapyramidal reactions.6In an effort to minimize acute nausea andvomiting in patients undergoing chemotherapywith ProMECE-CytaBOM, we designed a dou-ble-blind, cross-over study to compare the effi-cacy and safety of a LS-based and a MTC-basedantiemetic combination. We report here thefinal results of this study, concluded after 20consecutive patients had been enrolled.Patients and MethodsTwenty consecutive patients with histologicallyconfirmed, aggressive NHL scheduled to receiveP-C chemotherapy were enrolled. The character-istics of these patients are summarized in Table1. To be included in the study patients had to beat least 18 years of age, have received no priorCT treatments and be expected to receive at leastfour cycles of P-C. Exclusion criteria includednausea or vomiting or the use of antiemeticagents in the 24 hours before CT, severe concur-rent illness or other causes of vomiting, concur-rent use of benzodiazepines (except when givenfor night sedation), and radiotherapy. The studywas approved by the local Ethics Committees ofparticipating institutions and all patients gaveinformed consent.Study designIn this double-blind, cross-over study patientswere randomly assigned to two different anti-emetic programs. Patients assigned to Arm Awere to receive two initial cycles of a LS-basedantiemetic regimen followed by two cycles ofMTC-based therapy, while those in Arm Bwould be given two initial cycles of a MTC-basedregimen followed by two cycles of LS-based ther-apy. According to the study design each patientwould be treated with both antiemetic combina-tions but in a different sequence (LS32 →MTC32 or MTC32 → LS32.ProMECE-CytaBOM chemotherapyDay 1: cyclophosphamide 650 mg/m2; etopo-side 120 mg/m2; epidoxorubicin 30 mg/m2; day8: cytosine arabinoside 300 mg/m2; bleomycin 5mg/m2; vincristine 1.4 mg/m2; methotrexate 120mg/m2; prednisone 60 mg/m2 orally, day 1-14(except days 1 and 8 I.V.). ProMECE-CytaBOMwas delivered according to the scheme proposedby Fisher et al.1 except for doxorubicin whichwas replaced at a 20% higher dose by epidoxoru-bicin. Epidoxorubicin was preferred to doxoru-bicin in view of its lower cardiac toxicity at thesame tumor effectiveness.7Antiemetic regimenLevosulpiride-regimen → day 1: LS (0.5 mg/kgin 100 cc saline) over 15 minutes, 30 minutesbefore and 30 minutes after CT; prochlorper-azine (10 mg rectally) 30 minutes before CT; day8: chlordimethyldiazepam (1 mg orally) 45 min-utes before CT; LS (1 mg/kg in 100 cc saline)over 15 minutes, 30 minutes before and 30 min-utes after CT; promethazine (50 mg intramuscu-larly) 45 minutes before CT; prochlorperazine(10 mg rectally) 30 minutes before CT.Metoclopramide-regimen: → same combina-tion of drugs as Arm A, except LS was replacedwith MTC at the same dose.No other antiemetic agents were given duringthe 24 hours following chemotherapy. FoodPrevention of ProMECE-CytaBOM-induced emesisLEVO MTCNo. of courses % No. of courses  %age (yr) 50 1 11 3 27> 50 8 89 8 73performance status (WHO)0 1 12 8 731 4 44 2 192 4 44 1 8sexmale 3 33 4 36female 6 67 7 64Table 1. Patient characteristics.R. Sabbatini et al.418intake was forbidden in the 6 hours followingCT administration. Before discharge, patientswere asked about the tolerability of the therapyreceived. Twenty-four hours after the treatmentpatients were contacted by phone by a memberof the research team who recorded the numberof emetic episodes, nausea, and any otheradverse events.The efficacy, tolerability and safety of the anti-emetic regimens were recorded for each course(day 1 or day 8 of P-C) of chemotherapy. Response was defined according to the follow-ing criteria: complete protection (no emeticepisodes), partial protection (one to three emeticepisodes), or equivocal protection (four or moreemetic episodes). An emetic episode was definedas a single vomit or retching (vomit not produc-ing liquid) or any number of continuous vomitsor retching. Patients not responding to the anti-emetic regimens (i.e. 5 or more emetic episodesin any day after CT) received rescue medication(dexamethasone 8 mg intramuscularly, repeatedevery 12 hours as needed) and were removedfrom the study. The grade of nausea was assessed using the fol-lowing scale: none, no nausea; mild nausea, nointerference with normal daily life; moderatenausea, interference with normal daily life; andsevere, bedridden due to nausea. Nausea isdefined as the sensation of imminent vomiting.All data were analyzed with the StatisticalPackage for Social Sciences (SPSS).8 Differencesbetween groups were assessed using the chi-square test or Fisher’s exact test. Grades weregrouped when there were too few patients withhigher grades.ResultsSix patients in Arm A and 7 in Arm B com-pleted the planned four cycles of CT. In addition,3 patients in Arm A and 4 in Arm B received atleast one course of CT. Twenty-three courses (8 LS and 15 MTC)were not assessable due to reduced doses of theantineoplastic therapy. Thus a total of 137courses of antiemetic prophylaxis (70 courseson day 1 and 67 courses on day 8) were avail-able for the present analysis.NauseaOn day 1, no nausea was registered in 82% ofthe LS-based and 78% of the MTC-basedcourses, with no statistically significant differ-ences (p=0.386). On day 8, complete protectionwas achieved in 85% of the LS-based and 71%of MTC-based courses (p=0.238) (Table 2).VomitingOn day 1, complete protection from vomitingwas observed in 97% of the LS-based and in92% of the MTC-based courses. Differenceswere not significant (p=0.139). On day 8, com-plete protection was recorded in 88% and 85%of the LS and MTC-based courses, respectively(p=0.345) (Table 3).Complete protection from nausea wasobserved in 79% (108/137) of all courses, andcomplete protection from vomiting in 91%(124/137). Complete protection from nauseaand vomiting was achieved in 75% (103/137) ofall courses.Table 2. Protection from nausea.Day 1 Day 8No. of courses (%) No. of courses (%)grade of nausea LEVO MTC p LEVO MTC pnone 28 (82) 28 (78) 0.386 28 (85) 24 (71) 0.238mild 5 (15) 6 (17) 4 (12) 9 (26)moderate – 2 (5) – 1 (3)severe 1 (3) – 1 (3) –Table 3. Protection from vomiting.Day 1 DAY 8No. of courses (%) N. of courses (%)LEVO MTC p LEVO MTC pCP 33 (97) 33 (92) 0.139 29 (88) 29 (85) 0.345PP – 3 (8) 4 (12) 3 (9)EP 1 (3) – – 2 (6)CP: complete protection; PP: partial protection; EP: equivocal protection.Prevention of ProMECE-CytaBOM-induced emesis 419During the first two cycles of P-C no nauseawas registered in 76% (58/76) and no vomitingin 92% (70/76) of courses, respectively.Complete protection from nausea or vomitingwas achieved in 75% (57/76) of courses. Duringthe third and fourth cycles, complete protectionfrom nausea and vomiting was achieved in 82%(50/61) and 89% (54/61) of courses, respective-ly; complete protection from nausea or vomit-ing  was achieved in 75% (46/61) of courses. No nausea was observed in 84% (56/67) ofcourses with the LS-regimen and in 74%(52/70) of those with the MTC-regimen (p =0.183). As regards emetic episodes, completeprotection was recorded in 93% (62/67)  of  LS-regimen courses and in 89% (62/70) of thosewith the MTC-regimen (p=0.428). During the first two cycles 94% of patientstreated with LS and 77% of those treated withMTC experienced complete protection; the dif-ferences between the groups was not statisticallysignificant (p = 0.130). In patients treated withthe LS-based combination, a slight decrease inprotection from emesis was observed over thecourses. During the third and fourth cyclescomplete protection from nausea and vomitingwas observed in 75% of patients treated with LSand in 77% of those treated with MTC; howev-er,  cross-over did not modify the efficacy of theantiemetic regimens (Table 4).Both the LS- and MTC-based antiemeticcombinations were well tolerated, and adverseevents were mild (Table 5). However, a sub-setanalysis showed that on day 8, when antiemeticdrugs were used at a higher dose, the LS-basedregimen was associated with a statistically sig-nificant lower toxicity rate (p = 0.035). DiscussionControlling of emesis is an important goal inthe supportive care of patients with cancer. Thisrandomized, double-blind, cross-over studydemonstrated that the combination of chlor-dimethyldiazepam, prochlorperazine, promet-hazine,andLS is very effectiveagainst ProMECE-CytaBOM-induced nausea and vomiting.To our knowledge, this is the first studyreporting the efficacy of an antiemetic regimendesigned specifically for patients undergoingchemotherapy for NHL.ProMECE-CytaBOM is a moderately emeto-genic chemotherapy regimen comparable toother commonly used CT combinations con-taining an anthracycline and/or cyclophos-phamide. In a previous study we reported that acombination of metoclopramide and promet-hazine failed to control P-C-induced emesis inover 50% of patients.5 In that report we alsoobserved that drugs administered on day 8 ofDay 1 Day 8Cycle LS (%) MTC (%) LS (%) MTC (%)CP nausea 1 8 (89) 9 (82) 9 (100) 8 (73)2 8 (89) 7 (70) 5 (62) 4 (44)3 6 (67) 8 (100) 7 (78) 7 (87)4 6 (86) 5 (71) 7 (100) 4 (67)CP vomiting 1 9 (100) 10 (91) 9 (100) 10 (91)2 9 (100) 8 (80) 7 (87) 8 (89)3 8 (89) 8 (100) 8 (89) 7 (87)4 7 (100) 6 (86) 5 (71) 5 (83)CP nausea and 1 8 (89) 9 (82) 9 (100) 8 (73)vomiting 2 8 (89) 6 (60) 5 (62) 4 (44)3 6 (67) 8 (100) 6 (67) 6 (75)4 6 (86) 5 (71) 5 (71) 4 (67)Table 4. Cross-over evaluation of prophylaxis of ProMECE-CytaBOM-induced vomiting and nausea.Legend: CP: complete protection.Day 1No. of eventsDay 8No. of eventsLEVO MTC  p LEVO MTC pSedation – – 1 2Diarrhea 1 – – 1Confusion – – – 1Extrapyramidalreactions– 3 – 1Hot-flushes 1 – – 1Agitation 1 1 1 2Hiccupping 1 1 1 2Total 4 5 0.790 3 10Table 5. Adverse events.R. Sabbatini et al.420ProMECE-CytaBOM were  associated with ahigher incidence of emesis than those given onday 1, suggesting that the emetogenic potentialof the CT combination (cytarabine, vincristine,bleomycin and methotrexate) on day 8 might beschedule dependent. Therefore on day 8 of thisstudy patients were to receive a different anti-emetic scheme, with a higher dose of benzamide(LS or MTC) in addition to chlordimethyldia-zepam and promethazine.The complete protection from acute vomitingin 93% of courses achieved with LS and pro-chlorperazine on day 1, and with chlordime-thyldiazepam, LS, prochlorperazine andpromethazine on day 8 of ProMECE-CytaBOMshould be considered an extremely remarkableresult. Indeed, with serotonin receptor antago-nists (a newer class of antiemetic agents), therate of complete protection from emesis inpatients treated with cyclophosphamide (≥ 600mg/m2, in combination)- or anthracycline-based regimens usually does not exceed 70-86%.9-12Both levosulpiride, a selective dopamine (D2)receptor antagonist, and MTC have alreadybeen reported to be effective agents in the pre-vention of acute chemotherapy-inducedemesis.6,14 Moreover, LS exerts its antiemeticaction without sedation or extrapyramidalreactions, side effects which often complicatethe administration of MTC.14In the present study, adverse events with bothantiemetic combinations were mild; however,the percentage of patients experiencing sideeffects differed between the two groups. Thenumber of patients complaining of adverseexperiences on day 8 was significantly higher inthe MTC group (p = 0.035). In particular, nopatient in the LS group complained of extra-pyramidal reactions, whereas 6% of thosereceiving MTC (p = 0.148) experienced such areaction.Finally, it must be noted that the cost of thecombination used in the present study is verylow (less than $3 on day 1 and less than $6 onday 8), far less than that of low-dose serotoninantagonist-based regimens ($44 per day).In conclusion, the very high complete protec-tion rate, the absence of distressing extrapyra-midal reactions, and the low cost make the LS-based regimen particularly recommendable forpatients with aggressive NHL as prophylaxis ofProMECE-CytaBOM-induced acute nauseaand vomiting.References1. Fisher RI, De Vita VT Jr, Hubbard SM, et al. Randomizedtrial of ProMACE-MOPP vs. ProMACE-CytaBOM in previ-ously untreated, advanced stage, diffuse aggressive lym-phomas. Proc Am Soc Clin Oncol 1984; 3:242.2. Fisher RI, Ellen RG, Dahlerberg S, et al. Comparison of astandard regimen (CHOP) with three intensive chemothera-py regimens for advanced non-Hodgkin’s lymphoma. N EnglJ Med 1993; 328:1002-6.3. Miller TP, Dahlberg S, Weick JK, et al. Unfavourable histolo-gies of non-Hodgkin’s lymphoma treated with ProMACE-CytaBOM: a groupwide Southwest Oncology Group study. JClin Oncol 1990; 8:1951-8.4. Longo DL, De Vita VT Jr, Duffey PL, et al. Superiority ofProMACE-CytaBOM over ProMACE-MOPP in the treat-ment of advanced diffuse aggressive lymphoma: results of aprospective randomized trial. J Clin Oncol 1991; 9:25-38.5. Federico M, Moretti G, Gobbi PG, et al. ProMACE-Cyta-BOM versus MACOP-B in intermediate and high gradeNHL: preliminary results of a prospective randomized trial.Leukemia 1991; 5(Suppl 1):107-11.6. Zanoboni A, Forgione A, Oppizzi G, Zecca L. Effectiveness ofL(-)sulpiride in chemotherapy induced emesis. Chemio-terapia 1983; 2:311-6.7. Praga C, Intini C, Riva A. International experience with epi-doxorubicin in lymphomas (abstract). Proceedings of the 31stCongress of the Italian Society of Hematology, Italy, October4-8, 1987; I2:185.8. Nie NH, Hadlai Hull C, Jenkins J G. SPSS (Statistical Packagefor the Social Sciences). New York:Mc Graw-Hill, 1979.9. Bonneterre J, Chevallier B, Metz R, et al. A randomized dou-ble-blind comparation of ondansetron and metoclopramidein the prophylaxis of emesis induced by cyclophosphamide,fluorouracil, and doxorubicin or epirubicin chemotherapy. JClin Oncol 1990;8:1063-9.10. Buser KS, Joss RA, Piquet D, et al. Oral ondansetron in theprophylaxis of nausea and vomiting induced by cyclophos-phamide, fluorouracil, methotrexate (CMF) in women withbreast cancer: results of a prospective, randomized double-blind, placebo-controlled study. Ann Oncol 1993; 4:475-9.11. Jones AL, Hill AS, Soukop M, Hutcheon AW, Cassidy J.Comparison of dexamethasone and ondansetron in the pro-phylaxis of emesis induced by moderately emetogenicchemotherapy. Lancet 1991; 338:483-7.12. Michel Marty on behalf of the Granisetron Study Group. Acomparation of Granisetron as a single agent with conven-tional combination antiemetic therapies in the treatment ofcytostatic-induced emesis. Eur J Cancer 1992; 28(Suppl.1):S12-6.13. Campora E, Oliva C, Mammoliti S, et al. Oral ondansetron(GR 38032F) for the control of CMF-induced emesis in theoutpatient. Breast Cancer Res Treat 1991; 19:129-32. 14. De Jong J, Neuschwander H, Cavalli F, Bonollo L, Martini A.A randomized crossover clinical study on the effectiveness ofL-sulpiride in the prevention of nausea and emesis inducedby antiblastic chemotherapy. Curr Ther Res 1989; 46:707-16.

A RANDOMIZED, DOUBLE-BLIND, CROSS-OVER STUDY COMPARING A LEVOSULPIRIDE-BASED AND A METOCLOPRAMIDE-BASED COMBINATION IN THE PREVENTION OF PROMECE-CYTABOM-INDUCED EMESIS

A RANDOMIZED, DOUBLE-BLIND, CROSS-OVER STUDY COMPARING A LEVOSULPIRIDE-BASED AND A METOCLOPRAMIDE-BASED COMBINATION IN THE PREVENTION OF PROMECE-CYTABOM-INDUCED EMESIS

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