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Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: A double-blind randomized trial

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Protective effect of alpha-tocopherol in head and neck cancer radiation-induced mucositis: A double-blind randomized trial
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  PROTECTIVE EFFECT OF ALPHA-TOCOPHEROL IN HEADAND NECK CANCER RADIATION-INDUCED MUCOSITIS:A DOUBLE-BLIND RANDOMIZED TRIAL Paulo Renato Ferreira, MD, PhD, 1 James Freitas Fleck, MD, PhD, 2 Ada Diehl, MD, 3 Daniela Barletta, MD, 1 Aroldo Braga-Filho, MD, 1 Antonio Barletta, MD, 1 Ligia Ilha, MD 1 1 Department of Radiation Oncology, Hospital Sao Lucas da PUC, Pontificia Universidade Catolica do Rio Grande doSul (PUCRS), Av. Ipiranga 6690, Porto Alegre, RS 90610-000, Brazil. E-mail: prferreira@hcpa.ufrgs.br 2 Department of Clinical Oncology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grandedo Sul (UFRGS), Porto Alegre, RS, Brazil 3 Department of Cytopathology, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grandedo Sul (UFRGS), Porto Alegre, RS, Brazil  Accepted 15 October 2003  Published online 31 January 2004 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.10382  Abstract:  Background.  The study was designed to testwhether vitamin E (VE) provides oral mucosal protection inpatients with irradiated cancers of the head and neck. Methods.  Fifty-fourpatientswithcanceroftheoralcavityandoropharynx were randomly assigned to rinse the oral cavity in anoil solution containing either VE or placebo before every conven-tional fraction of 2 Gy and again 8 to 12 hours laterduring the 5 to7 weeks of radiotherapy (RT). Results.  Thirty-six events/167 patient-weeks (21.6%) and 54events/161patient-weeks(33.5%)ofsymptomaticmucositiswereobserved in VE and placebo groups, respectively ( p   = .038). VEreduced the risk by 36%. Subjective data at the end of thetreatment revealed that VE decreased pain grades 2 to 3 duringRT(3of28patientsvs14of26patients, p  =.0001).Nosignificantinfluence was detected in survival. Conclusion.  VE decreased the incidence of symptomaticoral radiation-induced mucositis in patients with cancer of theoropharynx and oral cavity.  A   2004 Wiley Periodicals, Inc.  Head Neck   26:  313–321, 2004 Keywords:  vitamin E; alpha-tocopherol; mucositis; radiotherapy;head and neck cancer V irtually all patients who receive radiotherapy(RT) to the head and neck area have mucosalcomplications develop. 1,2 The most troublesomeacute reaction for patients receiving RT to theoral cavity is radiation-induced mucositis, 3 whichnot only is painful but also may compromisetumor control by determining a decrease in doseintensity and interruptions of the treatment. 4,5 The pathogenesis of oral mucositis is not fullyunderstood, yet it is thought to involve direct andindirect mechanisms. 6 Direct mucosal injury Correspondence to:  P. R. Figueiredo FerreiraContact grant sponsor: Supported in part by Brazilian federal grants fromConselho Nacional de Pesquisas (CNPq).Presented at the American Society of Clinical Oncology (ASCO) 38thAnnual Meeting in Orlando, FL, on May 2002.This work has received IRB approval from Hospital Sao Lucas da PUCand Hospital de Clinicas de Porto Alegre.  B   2004 Wiley Periodicals, Inc. Vitamin E in Radiation-Induced Mucositis HEAD & NECK April 2004  313  by radiation interferes with the average 5-day to14-day turnover time of the oral epithelium. 7 It isgenerally believed that oral mucositis is aconsequence of the direct inhibitory effects of therapy on DNA replication and mucosal cellproliferation. 8 Indirect stomatotoxic effects resultfrom release of inflammatory mediators, loss of protective salivary constituents, and therapy-induced neutropenia. These events also promotethe emergence of bacteria, fungi, and viruses ondamaged mucosa. 9,10 There is considerable evi-dence indicating that the cytotoxic effects of ionizing radiation are mediated almost entirelyby radiation-induced oxygen free radicals. 11,12 These compounds also have been implicated asmediators of radiation-induced mucosal cell inju-ry, according to several experimental studies inanimals. 13–15  Alpha-tocopherol, the main constit-uent of vitamin E (VE), is the most impor-tant natural antioxidant present in the humanblood. 16 Its main biologic function is to scavengeperoxyl free radicals (HO2) in the cell membrane.Because of its free radical inactivation capabil-ities, VE has been evaluated in clinical trials as apotentially mucosal protective drug. It was usedas a primary agent in chemotherapy studies 17,18 and associated with other drugs in a chemo-radiation study. 13  A number of agents have been investigatedwith the purpose of preventing treatment-inducedmucositis, but their efficacy and safety have notbeen clearly established. 1,3,19 In a recent meta-analysis involving 15 eligible trials that testedseveral different drugs, no strong body of evidenceto support specific recommendations for the pre-vention of oral mucositis in clinical practice wasfound. 20 In an attempt to find an effective treat-ment with a relatively nontoxic and inexpensiveagent, we designed a study to test the hypo-thesis that VE, as a single drug, is able toprovide oral mucosal protection in patients withcancer of the head and neck treated with RT aloneor postoperatively. METHODSPatient Selection.  Patients with a confirmed his-tologic diagnosis of cancer of the oral cavity andoropharynx referred to RT were entered into thistrial. After evaluation at Hospital de Clinicas dePortoAlegre,UniversidadeFederaldoRioGrandedoSul(UFRGS),theyreceivedirradiationaloneorpostoperative radiotherapy at Hospital Sao Lucasda PUCRS, Pontificia Universidade Catolica doRio Grande do Sul (HSL-PUCRS) in Porto Alegre,Southern Brazil. Admission requirements con-sisted of: (1) a minimal irradiated buccal mucosalarea 12.2 cm 2 or greater; the limits of this area,measured on verification films, were the hard pa-late (superior),thefloorofthemouth(inferior),theanterior border of the vertical portion of themandible (posterior), and the distal border of the irradiation field (anterior); (2) age at least21 years. (3) Zubrod 21 performance status grade2orlower;(4)toleranceofsolidfoodatstudyentry;(5) no trismus, concomitant use of oral anti-coagulants, previous or current history of othercancers, previous history of RT in the head andneck area, or previous or concomitant chemothe-rapy. The initial evaluation consisted of a history,physical/otolaryngologic/dentalexamination,com-puted tomography of the head and neck, chestx-ray study, and complete blood count. Patientswere staged according to the UICC (Union Inter-nationale Contre le Cancer) TNM classification. 22 This study was approved by the Scientificand Bioethics Committees of both institutions inaccordance with the precepts established by theHelsinki Declaration. Informed consent was ob-tained from all patients. Randomization and Treatment Planning.  The ran-domization process was conducted by coworkersnot directly involved in this study. Patient’snames were picked out by lot and allocated in agrid with five blanks per line, according to thegroup of treatment: VE or placebo. Intermittently,the line sequences were changed to improve therandomization. Neither the authors nor patientswere aware of the identification of the prescribeddrugs. Patients were given either 400 mg of VE(Ephynal, Produtos Roche Quimicos e Farmaceu-ticos, Sao Paulo, SP, Brazil) or 500 mg of placebo(Efamol Pure Evening Primrose Oil, Kentville,NS, Canada). The drugs were availa-ble as an oilsolution enclosed in a capsule. Patients weretaught to dissolve it in saliva, rinse it all over theoral cavity for 5 minutes, and then swallow itimmediately before every session of irradiation,Monday through Friday, from the first to the lastday of RT. A second capsule was similarlyadministered at the patient’s home after 8 to12 hours. Both VE and placebo capsules had thesame size, shape, color, and texture and weregiven to the patients in vials supplied weekly. Thedrug used as a placebo is a combination of fattyacids (oleic, linoleic, gamma-linoleic, palmitic, HEAD & NECK April 2004 314  Vitamin E in Radiation-Induced Mucositis  stearic, and others) but also contains 2.5% of VEin its formula (13 IU per 500 mg capsule).Prescribed analgesics were paracetamol/codeineor dipyrone whenever necessary.RTwasprovidedbyaCobalt60unit(TheratronPhoenix) operating at 80-cm target-skin distance.Two parallel opposed fields were designed withcustomized alloy shielding blocks to include thetumor within a 2-cm safe margin and the uppercervical lymph nodes bilaterally. Anterior supra-clavicular fields were added whether metastaticcervical lymph nodes were present or the primarytumor was located in the tonsils or tongue. A dailydose of 2 Gy/section 5 days a week was calculatedat the midline up to a cumulative dose of 44 Gy/ 4.5 weeks. A first field reduction was made for thespinal cord, sparing up to the dose of 60 Gy/ 6 weeks. A second reduction was made to encom-pass only thetumor within 1-cm marginsuptothefinal dose of 70 Gy/7 weeks. Patients previouslytreated with complete or incomplete resectionswereplannedtoreceivetotaldosesof50or60Gyin5 and 6 weeks, respectively, with a similar tech-nique. Check films were obtained during patient Table 1.  Patient characteristics.No. patients (%) per treatment group.Characteristics Vitamin E Placebo  p   valueSex .999Male 25 (89.3) 23 (88.5)Female 3 (10.7) 3 (11.5)Age .268Mean (standard deviation) 53.5 (9.1) 57.3 (15.3)Histology .347Squamous cell carcinoma 26 (92.8) 21 (80.8)Undifferentiated carcinoma 1 (3.6) 4 (15.4)Adenoid cystic carcinoma 0 (0) 1 (3.8)Fibrosarcoma 1 (3.6) 0 (0)Anatomic site .789Tonsil 3 (10.7) 5 (19.2)Base of the tongue 4 (14.3) 2 (7.7)Retromolar trigone 3 (10.7) 2 (7.7)Soft palate 0 (0) 1 (3.8)Oral tongue 10 (35.7) 9 (34.6)Floor of the mouth 8 (28.6) 7 (26.9)Stage .142I 0 (0) 3 (11.5)II 4 (14.3) 7 (26.9)III 5 (17.8) 4 (15.4)IV 19 (67.9) 12 (46.2)Previous surgery .840Yes 18 (64.3) 17 (65.4)No 10 (35.7) 9 (34.6)Oral and dental evaluation .610Normal teeth and oral mucosa 5 (17.8) 10 (38.5)Single alterationsPeriodontal disease 5 (17.8) 4 (15.4)Increased coating of the tongue 3 (10.7) 1 (3.8)Fibrous hyperplasia 2 (7.1) 1 (3.8)Gingivitis 1 (3.6) 1 (3.8)Multiple alterationsPeriodontal disease, cavities, pericoronitis,fibrous hyperplasia, increase coating of the tongue8 (28.6) 4 (15.4)No evaluation 4 (14.3) 5 (19.2)Cigarette smoking historyYes 27 (96.4) 24 (92.3) .603No 1 (3.6) 2 (7.7)Alcohol history .878Yes 21 (75.0) 20 (77.0)No 7 (25.0) 6 (23.0)Vitamin E in Radiation-Induced Mucositis HEAD & NECK April 2004  315  setup and weekly for subsequent quality con-trol throughout RT. Protocol violations wereestablished when patients: (1) did not receive theprescribed dose of irradiation, (2) interrupted RTmore than three consecutive fractions, or (3) didnot take the protocol medications adequately. Oral Mucosal Evaluation.  A comprehensive den-tistry evaluation was made to ensure adequatebalancing of pretreatment conditions related tosecondary factors associated with mucositis se-verity. There was a previous mucositis gradingtraining with study participants to get scoringconsistency. Patients had their weight recordedand oral mucositis evaluated and graded by onlyone investigator (PRF) on the first day of RT andthen subsequently once a week until the lastfraction. TheRTOG/EORTC 23 (RadiationTherapyOncology Group/European Organization for Re-searchandTreatmentofCancer)objectivegradingsystem was used: grade 0, no changes over base-line; grade 1, injection; may experience mild pain;no analgesics required; grade 2, patchy mucositismay produce inflammatory serosanguineous dis-charge; may experience moderate pain requiringanalgesia; grade 3, confluent fibrinous mucositis;may experience severe pain requiring narcotic;grade 4, ulceration, hemorrhage, or necrosis. Forthe purposes of this study, symptomatic mucositiswas considered as grade 2 or higher. Gradingmucositis respected both aspects of pain intensityandobservablechangesinthemucosa.Toevaluatethe impact on quality of life, at the end of thetreatment patients filled out a questionnairebased on the World Health Organization Gradingof Mucositis/Stomatitis, 9 on which they reportedthe occurrence of pain and oral intake difficultyduring RT. This subjective grading system con-sisted of the following scale: grade 0, no pain;grade 1, painful mucositis, did not require mod-ificationsinoralintake;grade2,painfulmucositis,could eat but did require decrease in liquid intakeany time during RT; grade 3, painful mucositisprevented oral intake; grade 4, painful mucositisrequired parenteral or enteral support any timeduring RT. Statistics.  Themainendpointwastheseverityof oral mucositis. All randomly assigned patientswere counted for the analysis, according to theintention to treat principle. Not all the patientscompleted 7 weeks of RT, because some had hadprevious surgery and required lower doses of irradiation. ‘‘Patient-weeks’’ were defined as thenumberofpatientsatriskwhowereinthestudyinevery week of RT. For every patient-week, eachrecord of symptomatic buccal mucositis wasconsidered a single event. The number of eventsof symptomatic mucositis was correlated with thenumber of patient-weeks, aiming to take intoaccount the duration of time the patient had thetoxicity. An incidence density of symptomaticmucositis was calculated as a coefficient obtainedby the number of symptomatic mucositis eventsdivided by the number of patient-weeks in everyweek of RT. The study was designed to test amoderate to large effect. The expected sample sizewas estimated according to the method describedby Fleiss 24 on the basis of a 15% difference in thescores of symptomatic mucositis between VE andplacebo groups from a previous pilot study carriedout with 28 patients reported elsewhere. 25 Onehundred fifty-one patient-weeks were estimatedas necessary in each arm. A significant level of 5%andastatistical powerof80%wereadoptedtotestaminimalincidencedifferenceofatleast15eventsfor every 100 patient-weeks. Secondary end pointsweredurationofmucositisandweightloss.Forthe Table 2.  Events of symptomatic mucositis according to the radiotherapy week and the number of patient-weeks.Events of symptomatic mucositisVitamin E group ( n   = 28) Placebo group ( n   = 26)Week Patient-weeks No. events (%) Patient-weeks No. events (%)1 28 1 (3.6) 26 0 (0)2 28 4 (14.3) 26 7 (27.0)3 28 8 (28.6) 26 10 (38.5)4 27 8 (29.6) 26 11 (42.3)5 25 5 (20.0) 26 13 (50.0)6 23 8 (34.8) 21 9 (42.9)7 8 2 (25.0) 10 4 (40.0) Total 167 36 (21.6) 161 54 (33.5) HEAD & NECK April 2004 316  Vitamin E in Radiation-Induced Mucositis  same significance level, statistical power, andsample size, the estimated differences requiredfor the duration of symptomatic mucositis andweight loss between both groups were at least10 days and 11 kg, respectively.Pretreatment characteristics, as well as differ-ences in the intensity of mucositis and complica-tions, were analyzed by the Pearson’s chi-squaretest with a confidence interval of 95% (95% CI).Student’s  t   test and Mann-Whitney test were usedto compare differences between means and me-dians, respectively. Survival estimates were ob-tained by the Kaplan-Meier test 26 and the differ-ences between survival curves by the log ranktest. 27  All  p  values were two-tailed. SPSS 8.0 forWindows (SPSS Inc., Chicago, IL) was used asdatabase and for statistical calculation. RESULTSPatient Characteristics.  From December 1997 toDecember 1999, 54 patients were randomly as-signed: 28 to the VE group and 26 to the placebogroup. Frequencies of gender, age, histologic type,tumor location, stage, previous surgery, oral anddental evaluation, smoking, and alcohol consump-tion were similar in both arms (Table 1). Most of the patients were men. The mean age was55.4 years (standard deviation [SD] = 12.5). Themost frequent histologic and anatomic site weresquamous cell carcinoma and oral cavity, respec-tively. Forty patients had stages III and IV disease: 24 (85.7%) of 28 belonged to the VE groupand 16 (61.5%) of 26 to the placebo group (RR[relativerisk]=1.39;95%CI=0.99–1.96;  p =.086). Approximately two thirds of the patients had hadprevious surgery. Most of them had some type of oral or dental alteration (23 of 28 and 16 of 26patients in VE and placebo groups, respectively),and history of cigarette smoking and alcoholconsumption. Medication diaries were kept todocument compliance. Doses delivered out of totalplanned doses were 1560 (91.2%) of 1710 capsulesand 1610 of 1610 capsules (100%) in the VE andplacebogroups, respectively.Three patients in the VE group did not receive the prescribed doses: twobecause of intense mucositis and one because of death caused by tumor progression. The medianfollow-up of the 54 patients was 12 months (range,2–24 months). SurvivalRates.  At 2 years, the estimated overalland median survivals for all patients were 44.8%and 9.5 months (range, 2–24 months), respec-tively. For patients of the VE and placebo groups,these figures were 32.2% and 8.5 months (range,2–24 months) and 62.9% and 12.5 months(range, 2–23 months), respectively (   p  = .126). Severity of Mucositis.  All the patients had vary-ing degrees of mucositis develop during RT(Table 2). Symptomatic mucositis was more fre-quent in the placebo group than in the VE group:36 events of symptomatic mucositis were ob-served in 167 patient-weeks (21.6%) of the VEgroup, whereas 54 events of symptomatic muco-sitis were observed in 161 patient-weeks (33.5%)of the placebo group. These data were computedin the calculation of an incidence density (RR =0.643, 95 CI% = 0.42–0.98,  p  = .038) (Table 3). Accordingly, 8.3 patient-weeks were required for VE avoiding one event of symptomatic mucositis.Maximum peaks of symptomatic mucositis oc-curred at the sixth week and fifth week for the VE and placebo groups, respectively (Figure 1). As shown in Table 4, an analysis of thequestionnaires answered by patients at the endof the treatment also revealed that VE decreasedpain and restriction in oral intake (grades 2–3)during RT (3 of 28 patients = 10.7% vs 14 of 26patients = 53.8%) (   p  = .0001). Table 3.  Incidence density of symptomatic mucositis.No. eventsGroupSymptomaticmucositis Patient-weeksIncidence per 100patient-weeksVitamin E 36 167 21.6Placebo 54 161 33.5 RR=0.643, 95 Cl%, 0.42–0.98; p = .038. FIGURE 1.  Incidence density of symptomatic mucositis accordingto the week of radiotherapy. Vitamin E in Radiation-Induced Mucositis HEAD & NECK April 2004  317
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