Background High-dose isotretinoin therapy has been determinedto be an effective treatment for leukoplakia. However, a highrate of relapses and toxic reactions led us to conduct a trialof a much lower dose of isotretinoin in the hope of maintaininga response and limiting toxicity.
Methods In the first phase of the study, 70 patients with leukoplakiaunderwent induction therapy with a high dose of isotretinoin(1.5 mg per kilogram of body weight per day) for three months;in the second phase, patients with responses or stable lesionswere randomly assigned to maintenance therapy with either betacarotene (30 mg per day) or a low dose of isotretinoin (0.5mg per kilogram per day) for nine months.
Results In the first phase, the rate of response to high-doseinduction therapy in the 66 patients who could be evaluatedwas 55 percent (36 patients). The lesions of seven patientsprogressed, and therefore they did not participate in the secondphase of the trial. Of the 59 patients included in the secondphase, 33 were assigned to beta carotene therapy and 26 to low-doseisotretinoin therapy; these two groups did not differ significantlyin prognostic factors. Of the 53 patients who could be evaluated,22 in the low-dose isotretinoin group and 13 in the beta carotenegroup responded to maintenance therapy or continued to havestable lesions (92 percent vs. 45 percent, P<0.001). In situcarcinoma developed in one patient in each group, and invasivesquamous-cell carcinoma in five patients in the beta carotenegroup. Toxicity was generally mild, though greater in the groupgiven low-dose isotretinoin therapy.
Conclusions When preceded by high-dose induction therapy, low-doseisotretinoin therapy was significantly more active against leukoplakiathan beta carotene and was easily tolerated.
Leukoplakia is a premalignant lesion of the epithelium of theoral cavity; it is related to and can become oral cancer1,2.This lesion is closely linked etiologically to tobacco use,and its natural history is variable. The rate of transformationof leukoplakia into invasive cancer is directly related to thedegree of histologic abnormality. In the largest and longeststudy in the United States (mean follow-up, 7.2 years), thelong-term transformation rate for dysplastic lesions was 36percent3. Studies from other countries have found lower ratesfor the transformation of dysplasia into cancer (11 to 14 percent);however, these studies were shorter and suffered from the factthat transformation appears to occur at a constant rate peryear2. Leukoplakia can indicate the presence of field carcinogenesisor exposure to carcinogenic agents (primarily tobacco) throughoutthe entire length of the aerodigestive tract4,5.
The standard therapy for local dysplastic leukoplakic lesionsis surgical removal or laser ablation2,6. Standard local therapyis not feasible, however, when there are extensive multiplelesions, nor is it capable of reducing the risk of cancer associatedwith diffuse exposure to carcinogens throughout the aerodigestivetract.
There are strong clinical and investigational reasons for studyingthe use of systemic agents for leukoplakia. The high risk oftransformation of dysplastic leukoplakia and the number of patientsat high risk who are not helped by surgery provide the clinicalbasis for a trial of a chemopreventive approach7,8. The broaderrationale for this investigation rests on the relation of leukoplakiathrough field carcinogenesis to other tobacco-related epithelialcancers of the aerodigestive tract4,5,6,8. Excellent preclinicalmodels are available for studying oral carcinogenesis and interventionin this process8,9. Located in the oral cavity, leukoplakiacan be monitored easily and relatively noninvasively. It thereforeserves as an ideal in vivo human model for testing the potentialof chemopreventive agents throughout this region.
In 1986 a trial of isotretinoin (13-cis-retinoic acid) givenin a high dose for leukoplakia established the activity of thisdrug10. The wider clinical value of leukoplakia as a model wasconfirmed by a subsequent adjuvant trial of high-dose isotretinointherapy, which established this agent's substantial activityin preventing second primary tumors associated with head-and-neckcancer,11 tumors that are causally and biologically relatedto leukoplakia4,5,6,8.
The short-term (three month) trial reported in 1986 had twomajor problems: a relapse rate of more than 50 percent withintwo to three months after the end of therapy, and a level oftoxicity that was unacceptably high for general clinical usein chemoprevention10.
The present, longer trial (12 months) was designed to evaluatethe efficacy and toxic effects of a low dose of isotretinoinin maintaining the remission of oral precancer or halting itsprogression. The trial was conducted in two phases: a three-monthinduction phase in which patients took a high dose of isotretinoin,followed by a nine-month maintenance phase in which patientswith responses or stable lesions were randomly assigned eitherto treatment with a low dose of isotretinoin or to treatmentwith beta carotene.
The use of the retinoid isotretinoin is based on extensive datademonstrating the anticarcinogenic activity of retinoids inhumans5,6,7,8,10,11,12,13,14,15. Retinoids have reversed premalignantepithelial lesions5,6,7,8,10,12,14,15,16 and have helped toprevent second primary cancers of the skin17 and the head andneck8,11,15. The natural agent beta carotene was chosen as thecomparison drug for the maintenance phase because of its establishedlack of toxicity, epidemiologic data suggesting it has a rolein preventing squamous-cell carcinoma of the aerodigestive tract,and its variable activity against leukoplakia in several uncontrolledclinical trials6,8,18,19,20.
The final results of this randomized chemoprevention trial arepresented in this report.
Methods
Criteria for Eligibility
The three major criteria for inclusion were the presence oforal lesions that were histologically confirmed as premalignantand could be measured in two dimensions, normal renal and hepaticfunction, and acceptable fasting triglyceride levels at entry(levels <2.5 times the upper limit of normal). We primarilysought to include patients with dysplastic lesions, althoughpatients with extensive, symptomatic hyperplastic oral lesionsalso were eligible. The three major criteria for exclusion werethe possibility of pregnancy, a current intake of large dosesof vitamin A (>25,000 USP units per day) or beta carotene,and a history of oral cancer within the two years before thestudy. Physical examination and appropriate laboratory studieswere performed before treatment was started.
The nature and purpose of the study were fully discussed witheach patient. The study protocol was approved by our institutionalreview board for human research, and written informed consentwas obtained from all patients.
Study Design
This study had two phases. In the first phase, all patientsunderwent induction therapy with a high dose of isotretinoin(1.5 mg per kilogram of body weight per day) for three months.Patients whose lesions progressed during this period were withdrawnfrom the study. In the second phase, patients whose lesionsresponded to treatment or remained stable were stratified accordingto the histologic type of their lesions and the nature of theirresponse to induction therapy; they were then randomly assignedto maintenance therapy with either a low dose of isotretinoin(0.5 mg per kilogram per day) or beta carotene (30 mg per day)for nine months. The four strata were dysplasia, with a response;dysplasia, with no response; hyperplasia, with a response; andhyperplasia, with no response. Computer randomization (conductedby the Data Management Office of the Division of Medicine) groupedpatients in blocks of six within each stratum before they wereassigned to maintenance therapy. Patients whose lesions progressedat any time were withdrawn from the study.
Patients were evaluated for toxic reactions every four weeksduring both study phases. The criteria for grading toxicitywere based on the standards of the M.D. Anderson Cancer Center,21which include the Common Toxicity Criteria of the National CancerInstitute and others22. Grade 1 toxicity was mild (e.g., cheilitiseasily controlled with emollients); grade 2, moderate and tolerable(e.g., pruritus causing discomfort or generalized mild dermatitis);grade 3, severe and intolerable (e.g., conjunctivitis poorlycontrolled with artificial tears); and grade 4, most severeand life-threatening (e.g., generalized exfoliative dermatitiswith or without systemic infection).
Every four weeks, physical examinations and standard laboratorystudies were performed, and compliance with treatment was assessedby a review of daily calendars kept by the patients. If theexaminer suspected that the lesions had progressed, the patientwas referred to a dental oncologist for formal measurements.
The dose of isotretinoin (whether for induction or maintenance)was reduced substantially if toxicity of grade 2 or greaterdeveloped; the dose of beta carotene was not modified. Bothdrugs were provided in capsules (Hoffmann-LaRoche, Nutley, N.J.)and were taken orally.
Assessment of Response
The outcome of treatment was assessed both clinically and histologicallyby investigators other than the medical oncologist who evaluatedtoxicity. A dental oncologist evaluated the measurements andcolor photographs of the lesions in a blinded fashion to categorizeobjective clinical responses. These evaluations were carriedout at entry and in the 3rd and 12th (last) months of the study.Two-dimensional measurements, color photographs, and biopsyspecimens were also obtained whenever a patient had clinicalevidence of disease progression and left the study.
An objective response was considered complete when gross inspectionrevealed no evidence of a lesion, and it was considered partialwhen the size of a lesion or of the sum of the measurementsof all lesions decreased by at least 50 percent. Lesions wereconsidered stable when their sizes increased by less than 25percent or decreased by less than 50 percent. Disease progressionwas defined as an increase of at least 25 percent in the sumof the measurements of all lesions during treatment or as theappearance of any new lesion.
Histologic evaluations were performed at entry, after inductiontherapy, and at the completion of the study. All slides werecoded and interpreted in a blinded fashion by one pathologist,who used strict histologic criteria to grade dysplasia as mild,moderate, or severe10. A random selection of 20 percent of gradedtissue specimens was reviewed by a second pathologist to confirmthe consistency of the grading by the primary pathologist.
Statistical Analysis
The main statistical objective of this study was to comparethe rates of treatment failure in the two treatment groups assignedto maintenance therapy. Failure rates were calculated afterthe completion of induction and maintenance therapy. We plannedto enroll 60 patients so that if any patients were lost becauseof disease progression or withdrawal, each treatment group wouldcontain 25 patients who could be evaluated. This would allowthe rate of treatment failure to be estimated with a standarderror no greater than 10 percent.
Two-sample t-tests were used for analyses of continuous variables,such as age. Two-way contingency tables were formed and analyzedby the Pearson chi-square test for categorical variables, suchas disease progression and toxicity rates23. All P values aretwo-sided.
Results
Characteristics of the Patients
A total of 70 patients entered the study. Their important characteristicsand the histologic types of their leukoplakia are shown in Table 1.There were no significant differences between the maintenance-therapygroups in their major prognostic features at base line. Mostpatients were at high risk, as indicated by the high percentagewith dysplasia in each treatment group.
Sixty-six of the 70 enrolled patients could be evaluated fortheir responses to induction therapy (a high dose of isotretinoinfor three months); 3 of the other 4 patients could not be evaluatedbecause of noncompliance, and 1 because of toxicity-relatedwithdrawal. The percentage of patients with complete or partialclinical responses was 55 percent (95 percent confidence interval,42 to 67), and the percentage with stable disease was 35 percent.The degree of histologic dysplasia was reduced in 43 percent(18 of 42) of the patients with dysplasia who could be evaluated.Disease progression occurred in seven patients during the inductionphase, and they were withdrawn from the study immediately.
Induction therapy produced substantial toxic reactions. Sixty-eightpatients completed at least one month of therapy and could thereforebe evaluated for toxic reactions (Table 2). All of them hadat least low-grade toxic reactions, and many had two or morereactions. Thirteen patients had no more than grade 2 reactions;23 had grade 3 or 4 reactions, including 1 patient who was withdrawnbecause of intolerable gastrointestinal effects. No major livertoxicity occurred. Transient elevations of alkaline phosphataselevels indicating toxicity occurred in seven patients, and elevationsof aminotransferase levels occurred in four patients.
Table 2. Toxic Effects of High-Dose Isotretinoin Induction Therapy.
Maintenance Phase
Eleven of the 70 patients enrolled were withdrawn during theinduction phase (7 patients for disease progression, 3 for noncompliance,and 1 for toxicity). Fifty-nine patients who had responses orstable lesions by the end of induction therapy were randomlyassigned to maintenance therapy with beta carotene (33 patients)or a low dose of isotretinoin (26 patients). Six patients (fourtaking beta carotene and two taking isotretinoin) could notbe evaluated. One patient dropped out immediately after beingassigned to beta carotene, and five dropped out later for reasonsother than toxicity or disease progression. Fifty-three patients(29 taking beta carotene and 24 taking isotretinoin) could befully evaluated.
Because of an early error in dispensing by the pharmacy, subsequentlycorrected, the first 10 patients taking beta carotene receivedhalf the planned dose (15 instead of 30 mg per day) and 5 othersreceived half the planned dose (15 mg) initially and the fulldose (30 mg) for three to eight months. The remaining 14 patientstaking beta carotene received the full dose throughout the maintenancephase.
The clinical results of maintenance therapy are shown in Table 3.The rate of disease progression in the group taking a lowdose of isotretinoin was significantly lower than the rate inthe group taking beta carotene (8 percent vs. 55 percent, P<0.001).Conversely, the rate of further responses to maintenance therapywas higher in the isotretinoin group than in the beta carotenegroup (33 percent vs. 10 percent). Relapse (disease progression)occurred early in 8 of the 16 patients who were taking betacarotene (in 4 patients after three months of maintenance therapy,in 3 after five months, and in 1 after six months). Relapsealso occurred in two patients who were taking isotretinoin,but it was not detected before the final evaluation (at ninemonths).
Table 3. Final Clinical Results of Maintenance Therapy.
Within 28 months after maintenance therapy began, in situ cancerdeveloped in two patients, one in each treatment group, andinvasive squamous-cell carcinoma developed in five patientsin the beta carotene group. All seven patients underwent curativewide excision.
The outcomes of maintenance and induction therapy were not correlated.Whether a response occurred or lesions remained stable afterinduction therapy had little effect on the outcome of maintenancetherapy (Table 4).
Table 4. Rates of Disease Progression in the Maintenance Groups, According to the Outcome of the Induction Phase.
The results of maintenance therapy were not affected by tobaccouse -- that is, the rate of disease progression among patientstaking beta carotene who did not use tobacco was similar tothe rate among those who did. Tobacco use was recorded at entry;during the study, no active tobacco users quit completely andno nonusers started.
Final biopsies provided histologic results that could be comparedwith the final clinical results. In 23 (44 percent) of the 52patients who could be evaluated histologically (1 patient refuseda final biopsy) -- 4 with responses, 14 with stable lesions,and 5 with disease progression -- the histologic and clinicalresults were the same. The largest discrepancy occurred in 10patients who were shown clinically to have disease progressionbut shown histologically to have stable lesions. Also, six patientswith clinical responses had histologically stable disease.
The consistency of histologic grading was confirmed. By simplerandom sampling without replacement, a computer selected 12patients, 6 from each maintenance-phase group, whose biopsyspecimens were to be reviewed by a second pathologist not involvedin the study and blinded to the interpretations of the firstpathologist. These 12 patients had at least three sequentialbiopsies (at base line, after induction, and after maintenance),and 1 patient (at high risk) had five sequential biopsies. Atotal of 38 specimens were reviewed. The second and primarypathologists agreed about 35 specimens (92 percent) and disagreedabout 3 specimens, which the first pathologist interpreted asshowing hyperplasia and the second pathologist interpreted asshowing focal mild dysplasia.
Compliance during the maintenance phase was excellent; all evaluatedpatients took at least 80 percent of the planned doses, and62 percent (33 of 53) took at least 90 percent.
Maintenance-phase toxicity was relatively mild (Table 5). Fifty-eightpatients who completed at least one month of maintenance therapywere included in the toxicity analysis (26 taking isotretinoinand 32 taking beta carotene). One patient who dropped out ofthe study immediately after random assignment to beta carotenewas excluded. With respect to mucocutaneous toxicity, therewere no significant differences between the two treatment groupsin the rate of high-grade reactions (grade 3 or 4); there weresignificant differences favoring the beta carotene group inthe rate of low-grade reactions (grade 1 or 2). Hypertriglyceridemiaof grade 3 or 4 was more frequent in the isotretinoin group(P = 0.05). As in the induction phase, there were no major liverabnormalities. Reversible aminotransferase elevations occurredin two patients taking isotretinoin. Mild and reversible skinyellowing occurred in nine patients, all of whom were takingbeta carotene.
Of the 10 patients with grade 3 or 4 toxicity during inductiontherapy who were assigned to maintenance therapy with isotretinoin,2 also had grade 3 or 4 reactions (although reactions of differenttypes) during the maintenance phase and 8 had grade 1 or 2 reactions.Therefore, the occurrence of high-grade toxicity during inductiontherapy did not predict the occurrence of such toxicity duringlow-dose maintenance therapy. Many patients with low-grade reactions(grade 1 or 2) during induction therapy with isotretinoin hadsimilar low-grade reactions during maintenance therapy, indicatingthat the levels of toxicity did not escalate during the longer-term,low-dose phase.
Discussion
In 1986 high-dose isotretinoin therapy was shown to be highlyeffective against leukoplakia, but the toxicity of that regimenwas high, and over 50 percent of patients with responses relapsedwithin two to three months after therapy was stopped10. In thepresent study, the primary goal was to maintain or improve responsesor to prevent the progression of leukoplakia with a low doseof isotretinoin at an acceptable level of toxicity. The maintenancedose of isotretinoin -- 0.5 mg per kilogram per day, which isonly one third of the established high dose -- is the lowestsystemic dose of this agent ever studied in clinical trialsof leukoplakia.
In the induction phase, the 55 percent response rate for high-doseisotretinoin therapy was consistent with the established responserate of 67 percent10. In the maintenance phase, 92 percent ofthe patients assigned to low-dose isotretinoin therapy (22 of24) continued to respond or improved further (Table 3). Theresults of the maintenance phase were not affected by the outcomeof the high-dose isotretinoin induction therapy (Table 4). Thetoxicity of isotretinoin was clearly dose-related. The rateof grade 3 or 4 toxicity decreased from 34 percent during inductionwith a high dose of isotretinoin to only 12 percent during maintenancewith a low dose of isotretinoin. The analyses of efficacy andtoxicity during the maintenance phase indicate that a low doseof isotretinoin has a high therapeutic index for maintainingresponse (and preventing disease progression) in patients withoral premalignant lesions.
The overall rate of disease progression of 55 percent in thegroup taking beta carotene for maintenance was significantlyhigher than the rate of 8 percent in the group taking isotretinoin(P<0.001) (Table 3). These results do not show that betacarotene is effective as a maintenance agent in leukoplakia.Our study may have been biased in favor of isotretinoin becausemost patients selected for maintenance therapy were those shownto be sensitive to retinoids during induction therapy. Sucha bias was unavoidable in a trial designed primarily to prolongthe established short-term response to high-dose isotretinointreatment.
This trial used histologic assessments because of the potentiallycrucial role of histology in chemoprevention trials24. Strictmeasures were used to ensure the reliability of the evaluationof tissue specimens. The findings of a single primary pathologistwith extensive experience in head-and-neck cancer25,26 wereverified by random review by a second pathologist.
Discrepancies between histologic and clinical assessments occurred,primarily in patients whose lesions were stable histologicallybut had changed clinically. Such discrepancies may result morefrom differences in methods than from qualitative differencesin disease states -- for example, a reduction in a lesion by50 percent represented a clinical partial response althougha biopsy of the remaining visible lesion (i.e., not in an areaof tissue appearing grossly normal after a clinical response)might reveal no histologic change.
The role of tobacco in carcinogenesis in aerodigestive tractepithelia is beyond dispute6,27. The impact of tobacco on thesubsequent natural history of leukoplakia or the developmentof a second primary tumor (the leading cause of death, afterearly head-and-neck cancer28,29,30) is less clear2,3,5,8,11.Our previous studies10,11 and our present trial found no significanteffect of smoking or its cessation on the end points of oralpremalignant lesions or second primary tumors.
Recent data suggest that the biologic effects of retinoids aremediated by retinoic acid nuclear receptors. The sequencingof these receptors in the DNA-binding region indicates thatthey are members of the steroid-receptor superfamily31,32,33,34.It is known that isotretinoin can easily be isomerized to all-trans-retinoicacid, which is the known ligand for retinoic acid nuclear receptors.On the other hand, beta carotene is far removed from and noteasily metabolized into all-trans-retinoic acid. This differencebetween the two agents may contribute to differences in theirchemopreventive activity. Recent data suggest that retinoicacid receptors mediate the biologic effects of retinoids, specificallyin human oral leukoplakia35.
Supported by a Public Health Service grant (CA-46303) from theNational Cancer Institute. Dr. Lippman is the recipient of aClinical Oncology Career Development Award from the AmericanCancer Society.
We are indebted to Dr. Adel El-Naggar for his histologic review;to Becky Gossett, Rosanne Trost, and Karen McCarthy for theirclinical assistance; to Charles Earley for technical assistance;and to Stephanie Johnson and Sarita Jackson for their assistancein the preparation of the manuscript.
Source Information
From the Departments of Medical Oncology (S.M.L., W.K.H.), Pathology (J.G.B.), Dental Oncology (B.B.T., J.W.M.), Head and Neck Surgery (R.S.W., H.G.), and Biomathematics (J.J.L.), University of Texas M.D. Anderson Cancer Center; and the Department of Oral Diagnostic Sciences, University of Texas Health Science Center Dental Branch (G.L.H.) -- both in Houston.
Address reprint requests to Dr. Lippman at the Department of Medical Oncology, Box 80, University of Texas M.D., anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.
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Papadimitrakopoulou, V. A., William, W. N. Jr., Dannenberg, A. J., Lippman, S. M., Lee, J. J., Ondrey, F. G., Peterson, D. E., Feng, L., Atwell, A., El-Naggar, A. K., Nathan, C.-A., Helman, J. I., Du, B., Yueh, B., Boyle, J. O.
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Chen, X.-c., Wang, R., Zhao, X., Wei, Y.-q., Hu, M., Wang, Y.-s., Zhang, X.-w., Zhang, R., Zhang, L., Yao, B., Wang, L., Jia, Y.-q., Zeng, T.-t., Yang, J.-l., Tian, L., Kan, B., Lin, X.-j., Lei, S., Deng, H.-x., Wen, Y.-j., Mao, Y.-q., Li, J.
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Lippman, S. M., Lee, J. J., Martin, J. W., El-Naggar, A. K., Xu, X., Shin, D. M., Thomas, M., Mao, L., Fritsche, H. A. Jr., Zhou, X., Papadimitrakopoulou, V., Khuri, F. R., Tran, H., Clayman, G. L., Hittelman, W. N., Hong, W. K., Lotan, R.
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Lippman, S. M., Ki Hong, W.
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O'Shaughnessy, J. A., Kelloff, G. J., Gordon, G. B., Dannenberg, A. J., Hong, W. K., Fabian, C. J., Sigman, C. C., Bertagnolli, M. M., Stratton, S. P., Lam, S., Nelson, W. G., Meyskens, F. L., Alberts, D. S., Follen, M., Rustgi, A. K., Papadimitrakopoulou, V., Scardino, P. T., Gazdar, A. F., Wattenberg, L. W., Sporn, M. B., Sakr, W. A., Lippman, S. M., Von Hoff, D. D.
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Lippman, S. M., Spitz, M. R.
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Thaller, C., Shalev, M., Frolov, A., Eichele, G., Thompson, T. C., Williams, R. H., Dillioglugil, O., Kadmon, D.
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Shalev, M., Thompson, T. C., Frolov, A., Lippman, S. M., Hong, W. K., Fritsche, H., Kadmon, D.
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