Mucositis is still a leading side effect of high dose chemotherapy and irradiation delivered in autologous and allogeneic bone marrow transplantation. In this double blind randomised study, we tested the efficacy of sucralfate for the prevention of mucositis induced by such conditioning treatments. Treatment was started one day before conditioning regimen and patients were prospectively evaluated. The main endpoint was severe mucositis that was more frequent in the placebo group than in the sucralfate group (47% vs. 29%, P = 0.07). This trend was confirmed after adjustment on total body irradiation (TBI) (P = 0.06), the sole stratification parameter. Interestingly, patients receiving sucralfate showed a significant reduction of diarrhoea (25% vs. 53%, P = 0.005). Overall, the preventive administration of sucralfate appears to be an effective proce dure to diminish the occurrence of severe oral and intestinal mucositis in patients treated by high dose chemotherapy alone or combined with TBI before bone marrow transplantatio

Benhamou, E.

Brandes, I.

Castagna, L.

Dietrich, P.-Y

Forni, M.

Luboinski, M.

Pedraza, E.

Pico, J.-L

RERO DOC Digital Library

Annals of Oncology 12: 953-955. 2001.© 2001 Kluwer Academic Publishers. Printed in the Netherlands.Original articlePrevention of mucositis in bone marrow transplantation: A double blindrandomised controlled trial of sucralfateL. Castagna,1'4 E. Benhamou,2 E. Pedraza,1 M. Luboinski,2 M. Forni,3 I. Brandes,1J.-L.Pico1 & P.-Y.Dietrich1-3'Department of Haematology. BMTUntt. 2Biostatistws. Institut Gustave Roussy, Villejiiif France: 3Division of Oncology. University Hospital.Geneva. Switzerland; "Present address: Oncology-Hemalology Department. Istituto Climco Humanitas. Rozzano (MI), ItalySummaryMucositis is still a leading side effect of high dose chemo-therapy and irradiation delivered in autologous and allogeneicbone marrow transplantation. In this double blind randomisedstudy, we tested the efficacy of sucralfate for the prevention ofmucositis induced by such conditioning treatments. Treatmentwas started one day before conditioning regimen and patientswere prospectively evaluated. The main endpoint was severemucositis that was more frequent in the placebo group than inthe sucralfate group (47% vs. 29%, P = 0.07). This trend wasconfirmed after adjustment on total body irradiation (TBI)(P - 0.06), the sole stratification parameter. Interestingly,patients receiving sucralfate showed a significant reduction ofdiarrhoea (25% vs. 53%, P = 0.005). Overall, the preventiveadministration of sucralfate appears to be an effective proce-dure to diminish the occurrence of severe oral and intestinalmucositis in patients treated by high dose chemotherapy aloneor combined with TBI before bone marrow transplantation.Key words: mucositis, stem-cell transplantation, sucralfateIntroductionMucositis is a dose-limiting toxicity that frequentlycomplicates the course of autologous or allogeneic bonemarrow transplantations (BMT) [1]. Efforts should focuson its prevention, since treatment of established lesionsremains unsuccessful. Efficient prevention of toxic dam-age induced by conditioning regimens on intestinal mu-cosa will not only protect the patient from major pain,abdominal discomfort and diarrhoea, but could alsoimprove food intake and reduce the risk of infections bydiminishing the risk of microbial translocation from thedigestive tract into the bloodstream [2].Sucralfate is a complex salt of sucrose sulfate andaluminium hydroxide which is commonly used for thetreatment of acute duodenal and gastric ulcer diseases.Its main mechanism of action is thought to be theadhesion of the drug to ulcerated mucosa, forming aphysical barrier to protect them from acid, bile salts andpepsin. In addition, sucralfate has multiple biologicaleffects, such as the induction of prostaglandin andmucus production, an increase in mucosal blood flowand the binding of epithelial growth factor and basicfibroblastic growth factor to tissues [3]. This suggestedto us that this drug can be active in the prevention ofmucositis. We report the results of a monocentric pro-spective randomised double blind study designed toevaluate the efficacy of sucralfate to prevent mucositisafter BMT.Patients and methodsTreatmentPatients fulfilling the enrolment criteria (patients > 15 years old. hospi-talised for a allogeneic or autologous BMT. provision of a writteninformed consent) were randomly allocated to the sucralfate or theplacebo group, a few days before the beginning of the conditioningregimen. Conditioning regimens were categorised in four groups,based on their probability to induce mucositis (very high risk, highrisk, intermediate risk, low risk) (Table 1). Randomisation was strati-fied on Total Body Irradiation (TBI). Patients were instructed to ingestone dose package (2 g) of sucralfate or an identical-appearing placeboevery three hours daily and once during the night in case of wakening,for a maximum of seven mouthwashes per 24 hours. Sucralfate orplacebo were to be kept within the mouth for one minute before beingswallowed. Patients were asked to avoid drinking and eating during thefirst hour after treatment ingestion. Treatment was initiated after initialoral evaluation, one day before conditioning regimen and continueduntil bone marrow recovery (ANC > 0.5 x 106/l) or until the end ofmucositis (in the case of persistent mucositis after bone marrowrecovery).Patient evaluationPatients were examined twice weekly from the first day of conditioningregimen until bone marrow recovery or resolution of clinical signs ofmucositis. The clinical examination was performed by two physiciansonly, and results were prospectively recorded. The oral status wasscored according to a toxicity grading adapted from OMS criteria forgrafted patients (Table 2). The primary objective was to compare theoccurrence of severe stomatitis (grade 3-4). Secondary objectives wereto define (i) the duration of mucositis, (ii) the rate and severity ofdiarrhoea, and (iii) the caloric intake achieved by oral nutrition.954Table I. Patients' characteristics before inclusion in study.SexMaleFemaleDiagnosisALCMLNHLHDGerminal tumourOtherPrevious chemotherapy1 line2 lines3 lines4 linesPrevious radiotherapyPrevious mucositisConditioning regimenGroup 1Group 2Group 3Group 4Total body irradiationSingle dose (10 Gy)Hyperfractionated (14 Gy)OtherSucralfate// = 51 (%)343311 (22)4(8)15(29)9(18)4(8)8(16)50 (98)1820II114 (27)28 (57)52561530 (59)18(60)10(33)2(7)Placebon = 51 (%)343318 (35)5(10)10(20)4(8)6(12)8(16)50 (98)18235412 (24)35 (69)624101130 (59)16(53)10 (33)4(13)P-valueNSNSNSNSNSNSNSNSNSNSNSNSNSNSAbbreviations: AL - acute leukaemia: CML - chronic myelogenousleukaemia; NHL: non-Hodgkin lymphoma; HD - Hodgkin's disease,BMT - bone marrow transplantation; PBSC - peripheral blood stemcells; NS - not significant.Groups of conditioning regimens: Group I very high risk. TEC:TBI (single dose TBI at 10 Gy or hyperfractioned TB1 at 14 Gy) +cyclophosphamide (120 mg/kg) + etoposide (60 mg/kg); Group 2high risk TBI + cyclophosphamide (120 mg/kg), TBI + melpha-lan (140 mg/m2). TAM 12: TBI + cytarabine (12 g/m2) + melpha-lan (120 mg/m2). TL1 (total lymphoid irradiation) + cyclophospha-mide (120 mg/kg). Group 3 intermediate risk: BuCy: busulphan (16mg/kg) + cyclophosphamide (120 mg/kg), PEC: cisplatine (200 mg/m2) + cyclophosphamide (120 mg/kg) + etoposide (1800 mg/m2),CARBOPEC: carboplatine (800, 1200, or 1600 mg/m2) + cyclophos-phamide (120 mg/kg) + etoposide (1800 mg/m2). BusPAM: busul-phan (16 mg/kg) + melphalan (140 mg/m2), PAM: melphalanonly (140 mg/m2); Group 4 low risk. BEAM: BCNU (300 mg/m2) +etoposide (400 mg/m2) + cytarabine (400 mg/m2) + melphalan (140mg/m2) BEAC: BCNU (300 mg/m2) + etoposide (400 mg/m2) +cytarabine (400 mg/m2) + cyclophosphamide (120 mg/kg).Table 2 Adapted toxicity grading for evaluation of oral mucosa.Grade 0 No mucositisGrade 1 Erythema or whitish mucosaGrade 2 Superficial erosive lesions (< 20% of mucosa)Grade 3 Extensive erosive lesions or ulcerations or painfulswallowingGrade 4 Impossibility to swallow and/or to protrude thetongueGrade 0, I, 2 were grouped as 'mild' and grade 3. 4 as 'severe'Statistical methodsIt was estimated that 100 patients should be included to demonstrate aminimal difference of 35% in the rate of severe mucositis (two tailedtest, a = 5%, (? = 5%). Analyses were carried out on the intention-to-treat principle. Differences between groups were evaluated by x2 test orFisher's exact test for categorical variables and Student's /-test forcontinuous variables (two-sided tests). Cumulative mucositis rateswere estimated by the Kaplan-Meier method and the correspondingcurves were compared by the log-rank test. This study was approved bylocal and institutional ethical committees.ResultsPatients entered this trial from April 1991 to November1993. A total of 105 patients were randomised, 53 in thesucralfate arm and 52 in the placebo arm. Three patientscould not be included in the analysis because of recur-rence of haematological disease after randomisation(two in sucralfate and one in placebo group). The analy-sis was thus performed on 51 patients in each group.Baseline characteristics in the two groups were similar(Table 1), in particular the number of previous therapiesand the type of conditioning regimens. Although theincidence of mucositis of any grade was similar in botharms (84% in the sucralfate arm versus 88% in theplacebo arm), the proportion of patients with grade 3-4oral mucositis was higher in the placebo group than inthe sucralfate group (47% vs. 29%, P = 0.07). An elevatedproportion of grade 3/4 mucositis was also observed inallografted patients (82% vs. 17% for autografted pa-tients, P< 0.0001), and in patients treated by TBI (50%vs. 21%, P<0.01). After adjustment on TBI (the solestratification parameter), the P-value comparing thefrequence of grade 3-4 mucositis in the sucralfate andthe placebo arms was 0.06. Acute GvHD was diag-nosed in 57% of patients (8 of 14) in the sucralfate armand 47% (8 of 17) in the placebo arm, with upperdigestive tract involvement in three cases (two cases inthe sucralfate group and one case in the placebo group).The incidence of oral mucositis was not significantlyinfluenced by acute GVHD and the growth factorsadministration.Interestingly, we observed a highly significant decreaseof the occurrence of diarrhoea in the sucralfate group(25% vs. 53%, P = 0.005). Finally, sucralfate treatmentcan favour the recovery of enteral alimentation, with, atthe fourth week post-graft, a mean caloric intake of 647Kcal in the sucralfate group compared with 409 in theplacebo group (P - 0.04). No difference was notedconcerning the duration of oral mucositis, the incidenceof vomiting, gastrointestinal haemorrhage, or septicae-mia, as well as the use of antibiotics, antivirals, andanalgesic drugs (data not shown). The actuarial survival,evaluated from the first day of randomisation until bonemarrow recovery, was similar in both groups.955ConclusionIn this prospective monocentric randomised study, thepreventive administration of sucralfate appeared to effi-ciently diminish the discomfort induced by conditioningregimen of BMT, with less patients suffering from diar-rhoea. A trend was also observed (P = 0.06) for adiminution of severe stomatitis. The difference betweenplacebo and sucralfate groups concerning this endpointwas not as important as anticipated, because the rate ofsevere mucositis was lower than expected in the placebogroup. This was probably due to the protective effectsmediated by mechanical mouth washes with placebosolution that allow the repeated removal of drugs elim-inated in the saliva. The impressive reduction of diarrhoeacould appear as more surprising, but can be explainedby the well established intestinal cytoprotector proper-ties of swallowed sucralfate [4]. The overall results ob-tained in this preventive study confirm and extend whatwas observed in a previous randomised study testingsucralfate for the prevention of chemotherapy-inducedmucositis, in which a significant reduction in oedema,erythema and ulceration was reported in a low numberof evaluable patients receiving a combination of 5-fluo-rouracil and cisplatin [5]. In contrast, the results of arecent randomised double-blind study indicated thatsucralfate was not effective to treat 5-fluorouracil sto-matitis, without any difference between the investiga-tional and the placebo arms [6]. However, in this lasttrial, sucralfate was not administered as a prophylacticprocedure, but only in patients developing mucositisdespite an effective preventive cryotherapy with ice chips[7]. Furthermore, stomatitis was evaluated by historicalmeans and not in a prospective manner as in the presentwork.In conclusion, although sucralfate is probably poorlyactive to treat established mucosal damage induced bycytotoxic drugs, it appears to be an effective drug for theprevention of severe oral and intestinal mucositis inpatients treated by high dose chemotherapy (and TBI)before BMT. The long-term (several weeks) administra-tion of sucralfate is difficult in this setting, due to theimportant nausea occurring after BMT. Further clinicalresearch should determine whether a short-term (one ortwo weeks) prophylactic administration can also protectthe patient from this severe side effect.AcknowledgementsWe would like to thank the entire nursing staff ofBMT Unit for their enthusiastic collaboration and PaulRichard Walker for critical reading of the manuscript.References1. Wardley AM, Jayson GC Swindell R et al. Prospective evaluationof oral mucositis in patients receiving myeloablative conditioningregimens and haemopoietic progenitor rescue. Br J Haemalol2000; 110:292-9.2. Rapoport AP, Miller Watelet LF et al. Analysis of factors thatcorrelate with mucositis in recipients of autologous and allogeneicstem-cell transplants. J Clin Oncol 1999; 17: 2446-53.3. McCarthy DM. Sucralfate. N Engl J Med 1991; 325: 1017-25.4. Henriksson R, Franzen L. Littbrand B. Effects of sucralfate onacute and late bowel discomfort following radiotherapy of pelviccancer. J Clin Oncol 1992; 10: 969-75.5. Pfeiffer P. Hansen O. Madsen EL et al. Effects of prophylacticsucralfate suspension on stomatitis induced by cancer chemo-therapy. A randomized, double-blind crossover study. Acta Oncol1990; 29: 471-3.6. Loprinzi CL, Ghosh C, Camoriano J. et al. Phase III controlledevaluation of sucralfate to alleviate stomatitis in patients receivingfluorouracil-based chemotherapy. J Clin Oncol 1997; 15: 1235-8.7. Mahood DJ, Dose AM, Loprinzi CL, et al. Inhibition of fluorour-acil-induced stomatitis by oral cryotherapy. J Clin Oncol 1991; 9:449-52.Received 19 December 2000; accepted 16 March 2001.Correspondence to:Pierre-Yves Dietrich, MDHopital UniversitaireDivision d'Oncologie1211 Geneve 14SwitzerlandE-mail: pierre-yves.dietnch@hcuge.ch

Prevention of mucositis in bone marrow transplantation: A double blind randomised controlled trial of sucralfate

Prevention of mucositis in bone marrow transplantation: A double blind randomised controlled trial of sucralfate

Abstract

Similar works

Full text

Available Versions

RERO DOC Digital Library