Original Article
Comparison of Low-Dose Isotretinoin with Beta Carotene to Prevent Oral Carcinogenesis
N Engl J Med 1993; 328:15-20January 7, 1993
- Abstract
Background
High-dose isotretinoin therapy has been determined to be an effective treatment for leukoplakia. However, a high rate of relapses and toxic reactions led us to conduct a trial of a much lower dose of isotretinoin in the hope of maintaining a response and limiting toxicity.
Methods
In the first phase of the study, 70 patients with leukoplakia underwent 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 lesions were randomly assigned to maintenance therapy with either beta carotene (30 mg per day) or a low dose of isotretinoin (0.5 mg per kilogram per day) for nine months.
Results
In the first phase, the rate of response to high-dose induction therapy in the 66 patients who could be evaluated was 55 percent (36 patients). The lesions of seven patients progressed, and therefore they did not participate in the second phase of the trial. Of the 59 patients included in the second phase, 33 were assigned to beta carotene therapy and 26 to low-dose isotretinoin therapy; these two groups did not differ significantly in prognostic factors. Of the 53 patients who could be evaluated, 22 in the low-dose isotretinoin group and 13 in the beta carotene group responded to maintenance therapy or continued to have stable lesions (92 percent vs. 45 percent, P<0.001). In situ carcinoma developed in one patient in each group, and invasive squamous-cell carcinoma in five patients in the beta carotene group. Toxicity was generally mild, though greater in the group given low-dose isotretinoin therapy.
Conclusions
When preceded by high-dose induction therapy, low-dose isotretinoin therapy was significantly more active against leukoplakia than beta carotene and was easily tolerated.
Media in This Article
Table 1
Major Characteristics of the Patients.Table 2
Toxic Effects of High-Dose Isotretinoin Induction Therapy.Article Activity
- Article
Leukoplakia is a premalignant lesion of the epithelium of the oral 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 transformation of leukoplakia into invasive cancer is directly related to the degree of histologic abnormality. In the largest and longest study in the United States (mean follow-up, 7.2 years), the long-term transformation rate for dysplastic lesions was 36 percent3. Studies from other countries have found lower rates for the transformation of dysplasia into cancer (11 to 14 percent); however, these studies were shorter and suffered from the fact that transformation appears to occur at a constant rate per year2. Leukoplakia can indicate the presence of field carcinogenesis or exposure to carcinogenic agents (primarily tobacco) throughout the entire length of the aerodigestive tract4,5.
The standard therapy for local dysplastic leukoplakic lesions is surgical removal or laser ablation2,6. Standard local therapy is not feasible, however, when there are extensive multiple lesions, nor is it capable of reducing the risk of cancer associated with diffuse exposure to carcinogens throughout the aerodigestive tract.
There are strong clinical and investigational reasons for studying the use of systemic agents for leukoplakia. The high risk of transformation of dysplastic leukoplakia and the number of patients at high risk who are not helped by surgery provide the clinical basis for a trial of a chemopreventive approach7,8. The broader rationale for this investigation rests on the relation of leukoplakia through field carcinogenesis to other tobacco-related epithelial cancers of the aerodigestive tract4-6,8. Excellent preclinical models are available for studying oral carcinogenesis and intervention in this process8,9. Located in the oral cavity, leukoplakia can be monitored easily and relatively noninvasively. It therefore serves as an ideal in vivo human model for testing the potential of chemopreventive agents throughout this region.
In 1986 a trial of isotretinoin (13-cis-retinoic acid) given in a high dose for leukoplakia established the activity of this drug10. The wider clinical value of leukoplakia as a model was confirmed by a subsequent adjuvant trial of high-dose isotretinoin therapy, which established this agent's substantial activity in preventing second primary tumors associated with head-and-neck cancer,11 tumors that are causally and biologically related to leukoplakia4-6,8.
The short-term (three month) trial reported in 1986 had two major problems: a relapse rate of more than 50 percent within two to three months after the end of therapy, and a level of toxicity that was unacceptably high for general clinical use in chemoprevention10.
The present, longer trial (12 months) was designed to evaluate the efficacy and toxic effects of a low dose of isotretinoin in maintaining the remission of oral precancer or halting its progression. The trial was conducted in two phases: a three-month induction phase in which patients took a high dose of isotretinoin, followed by a nine-month maintenance phase in which patients with responses or stable lesions were randomly assigned either to treatment with a low dose of isotretinoin or to treatment with beta carotene.
The use of the retinoid isotretinoin is based on extensive data demonstrating the anticarcinogenic activity of retinoids in humans5-8,10-15. Retinoids have reversed premalignant epithelial lesions5-8,10,12,14-16 and have helped to prevent second primary cancers of the skin17 and the head and neck8,11,15. The natural agent beta carotene was chosen as the comparison drug for the maintenance phase because of its established lack of toxicity, epidemiologic data suggesting it has a role in preventing squamous-cell carcinoma of the aerodigestive tract, and its variable activity against leukoplakia in several uncontrolled clinical trials6,8,18-20.
The final results of this randomized chemoprevention trial are presented in this report.
Methods
Criteria for Eligibility
The three major criteria for inclusion were the presence of oral lesions that were histologically confirmed as premalignant and could be measured in two dimensions, normal renal and hepatic function, and acceptable fasting triglyceride levels at entry (levels <2.5 times the upper limit of normal). We primarily sought to include patients with dysplastic lesions, although patients with extensive, symptomatic hyperplastic oral lesions also were eligible. The three major criteria for exclusion were the possibility of pregnancy, a current intake of large doses of vitamin A (>25,000 USP units per day) or beta carotene, and a history of oral cancer within the two years before the study. Physical examination and appropriate laboratory studies were performed before treatment was started.
The nature and purpose of the study were fully discussed with each patient. The study protocol was approved by our institutional review board for human research, and written informed consent was obtained from all patients.
Study Design
This study had two phases. In the first phase, all patients underwent 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 withdrawn from the study. In the second phase, patients whose lesions responded to treatment or remained stable were stratified according to the histologic type of their lesions and the nature of their response to induction therapy; they were then randomly assigned to 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; and hyperplasia, with no response. Computer randomization (conducted by the Data Management Office of the Division of Medicine) grouped patients in blocks of six within each stratum before they were assigned to maintenance therapy. Patients whose lesions progressed at any time were withdrawn from the study.
Patients were evaluated for toxic reactions every four weeks during both study phases. The criteria for grading toxicity were based on the standards of the M.D. Anderson Cancer Center,21 which include the Common Toxicity Criteria of the National Cancer Institute and others22. Grade 1 toxicity was mild (e.g., cheilitis easily 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 poorly controlled with artificial tears); and grade 4, most severe and life-threatening (e.g., generalized exfoliative dermatitis with or without systemic infection).
Every four weeks, physical examinations and standard laboratory studies were performed, and compliance with treatment was assessed by a review of daily calendars kept by the patients. If the examiner suspected that the lesions had progressed, the patient was 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 greater developed; the dose of beta carotene was not modified. Both drugs 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 histologically by investigators other than the medical oncologist who evaluated toxicity. A dental oncologist evaluated the measurements and color photographs of the lesions in a blinded fashion to categorize objective clinical responses. These evaluations were carried out at entry and in the 3rd and 12th (last) months of the study. Two-dimensional measurements, color photographs, and biopsy specimens were also obtained whenever a patient had clinical evidence of disease progression and left the study.
An objective response was considered complete when gross inspection revealed no evidence of a lesion, and it was considered partial when the size of a lesion or of the sum of the measurements of all lesions decreased by at least 50 percent. Lesions were considered stable when their sizes increased by less than 25 percent or decreased by less than 50 percent. Disease progression was defined as an increase of at least 25 percent in the sum of the measurements of all lesions during treatment or as the appearance of any new lesion.
Histologic evaluations were performed at entry, after induction therapy, and at the completion of the study. All slides were coded 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 graded tissue specimens was reviewed by a second pathologist to confirm the consistency of the grading by the primary pathologist.
Statistical Analysis
The main statistical objective of this study was to compare the rates of treatment failure in the two treatment groups assigned to maintenance therapy. Failure rates were calculated after the completion of induction and maintenance therapy. We planned to enroll 60 patients so that if any patients were lost because of disease progression or withdrawal, each treatment group would contain 25 patients who could be evaluated. This would allow the rate of treatment failure to be estimated with a standard error 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 analyzed by the Pearson chi-square test for categorical variables, such as disease progression and toxicity rates23. All P values are two-sided.
Results
Characteristics of the Patients
A total of 70 patients entered the study. Their important characteristics and the histologic types of their leukoplakia are shown in Table 1Table 1
Major Characteristics of the Patients.. There were no significant differences between the maintenance-therapy groups in their major prognostic features at base line. Most patients were at high risk, as indicated by the high percentage with dysplasia in each treatment group.Induction Phase
Sixty-six of the 70 enrolled patients could be evaluated for their responses to induction therapy (a high dose of isotretinoin for three months); 3 of the other 4 patients could not be evaluated because of noncompliance, and 1 because of toxicity-related withdrawal. The percentage of patients with complete or partial clinical 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 induction phase, and they were withdrawn from the study immediately.
Induction therapy produced substantial toxic reactions. Sixty-eight patients completed at least one month of therapy and could therefore be evaluated for toxic reactions (Table 2Table 2
Toxic Effects of High-Dose Isotretinoin Induction Therapy.). All of them had at least low-grade toxic reactions, and many had two or more reactions. Thirteen patients had no more than grade 2 reactions; 23 had grade 3 or 4 reactions, including 1 patient who was withdrawn because of intolerable gastrointestinal effects. No major liver toxicity occurred. Transient elevations of alkaline phosphatase levels indicating toxicity occurred in seven patients, and elevations of aminotransferase levels occurred in four patients.Maintenance Phase
Eleven of the 70 patients enrolled were withdrawn during the induction phase (7 patients for disease progression, 3 for noncompliance, and 1 for toxicity). Fifty-nine patients who had responses or stable lesions by the end of induction therapy were randomly assigned to maintenance therapy with beta carotene (33 patients) or a low dose of isotretinoin (26 patients). Six patients (four taking beta carotene and two taking isotretinoin) could not be evaluated. One patient dropped out immediately after being assigned to beta carotene, and five dropped out later for reasons other than toxicity or disease progression. Fifty-three patients (29 taking beta carotene and 24 taking isotretinoin) could be fully evaluated.
Because of an early error in dispensing by the pharmacy, subsequently corrected, the first 10 patients taking beta carotene received half the planned dose (15 instead of 30 mg per day) and 5 others received half the planned dose (15 mg) initially and the full dose (30 mg) for three to eight months. The remaining 14 patients taking beta carotene received the full dose throughout the maintenance phase.
The clinical results of maintenance therapy are shown in Table 3Table 3
Final Clinical Results of Maintenance Therapy.. The rate of disease progression in the group taking a low dose of isotretinoin was significantly lower than the rate in the group taking beta carotene (8 percent vs. 55 percent, P<0.001). Conversely, the rate of further responses to maintenance therapy was higher in the isotretinoin group than in the beta carotene group (33 percent vs. 10 percent). Relapse (disease progression) occurred early in 8 of the 16 patients who were taking beta carotene (in 4 patients after three months of maintenance therapy, in 3 after five months, and in 1 after six months). Relapse also occurred in two patients who were taking isotretinoin, but it was not detected before the final evaluation (at nine months).Within 28 months after maintenance therapy began, in situ cancer developed in two patients, one in each treatment group, and invasive squamous-cell carcinoma developed in five patients in the beta carotene group. All seven patients underwent curative wide excision.
The outcomes of maintenance and induction therapy were not correlated. Whether a response occurred or lesions remained stable after induction therapy had little effect on the outcome of maintenance therapy (Table 4Table 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 tobacco use -- that is, the rate of disease progression among patients taking beta carotene who did not use tobacco was similar to the rate among those who did. Tobacco use was recorded at entry; during the study, no active tobacco users quit completely and no nonusers started.
Final biopsies provided histologic results that could be compared with the final clinical results. In 23 (44 percent) of the 52 patients who could be evaluated histologically (1 patient refused a final biopsy) -- 4 with responses, 14 with stable lesions, and 5 with disease progression -- the histologic and clinical results were the same. The largest discrepancy occurred in 10 patients who were shown clinically to have disease progression but shown histologically to have stable lesions. Also, six patients with clinical responses had histologically stable disease.
The consistency of histologic grading was confirmed. By simple random sampling without replacement, a computer selected 12 patients, 6 from each maintenance-phase group, whose biopsy specimens were to be reviewed by a second pathologist not involved in the study and blinded to the interpretations of the first pathologist. These 12 patients had at least three sequential biopsies (at base line, after induction, and after maintenance), and 1 patient (at high risk) had five sequential biopsies. A total of 38 specimens were reviewed. The second and primary pathologists agreed about 35 specimens (92 percent) and disagreed about 3 specimens, which the first pathologist interpreted as showing hyperplasia and the second pathologist interpreted as showing focal mild dysplasia.
Compliance during the maintenance phase was excellent; all evaluated patients took at least 80 percent of the planned doses, and 62 percent (33 of 53) took at least 90 percent.
Maintenance-phase toxicity was relatively mild (Table 5Table 5
Toxic Effects of Maintenance Therapy.). Fifty-eight patients who completed at least one month of maintenance therapy were included in the toxicity analysis (26 taking isotretinoin and 32 taking beta carotene). One patient who dropped out of the study immediately after random assignment to beta carotene was excluded. With respect to mucocutaneous toxicity, there were no significant differences between the two treatment groups in the rate of high-grade reactions (grade 3 or 4); there were significant differences favoring the beta carotene group in the rate of low-grade reactions (grade 1 or 2). Hypertriglyceridemia of grade 3 or 4 was more frequent in the isotretinoin group (P = 0.05). As in the induction phase, there were no major liver abnormalities. Reversible aminotransferase elevations occurred in two patients taking isotretinoin. Mild and reversible skin yellowing occurred in nine patients, all of whom were taking beta carotene.Of the 10 patients with grade 3 or 4 toxicity during induction therapy who were assigned to maintenance therapy with isotretinoin, 2 also had grade 3 or 4 reactions (although reactions of different types) during the maintenance phase and 8 had grade 1 or 2 reactions. Therefore, the occurrence of high-grade toxicity during induction therapy did not predict the occurrence of such toxicity during low-dose maintenance therapy. Many patients with low-grade reactions (grade 1 or 2) during induction therapy with isotretinoin had similar low-grade reactions during maintenance therapy, indicating that 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 highly effective against leukoplakia, but the toxicity of that regimen was high, and over 50 percent of patients with responses relapsed within two to three months after therapy was stopped10. In the present study, the primary goal was to maintain or improve responses or to prevent the progression of leukoplakia with a low dose of isotretinoin at an acceptable level of toxicity. The maintenance dose of isotretinoin -- 0.5 mg per kilogram per day, which is only one third of the established high dose -- is the lowest systemic dose of this agent ever studied in clinical trials of leukoplakia.
In the induction phase, the 55 percent response rate for high-dose isotretinoin therapy was consistent with the established response rate of 67 percent10. In the maintenance phase, 92 percent of the patients assigned to low-dose isotretinoin therapy (22 of 24) continued to respond or improved further (Table 3). The results of the maintenance phase were not affected by the outcome of the high-dose isotretinoin induction therapy (Table 4). The toxicity of isotretinoin was clearly dose-related. The rate of grade 3 or 4 toxicity decreased from 34 percent during induction with a high dose of isotretinoin to only 12 percent during maintenance with a low dose of isotretinoin. The analyses of efficacy and toxicity during the maintenance phase indicate that a low dose of isotretinoin has a high therapeutic index for maintaining response (and preventing disease progression) in patients with oral premalignant lesions.
The overall rate of disease progression of 55 percent in the group taking beta carotene for maintenance was significantly higher than the rate of 8 percent in the group taking isotretinoin (P<0.001) (Table 3). These results do not show that beta carotene is effective as a maintenance agent in leukoplakia. Our study may have been biased in favor of isotretinoin because most patients selected for maintenance therapy were those shown to be sensitive to retinoids during induction therapy. Such a bias was unavoidable in a trial designed primarily to prolong the established short-term response to high-dose isotretinoin treatment.
This trial used histologic assessments because of the potentially crucial role of histology in chemoprevention trials24. Strict measures were used to ensure the reliability of the evaluation of tissue specimens. The findings of a single primary pathologist with extensive experience in head-and-neck cancer25,26 were verified by random review by a second pathologist.
Discrepancies between histologic and clinical assessments occurred, primarily in patients whose lesions were stable histologically but had changed clinically. Such discrepancies may result more from differences in methods than from qualitative differences in disease states -- for example, a reduction in a lesion by 50 percent represented a clinical partial response although a biopsy of the remaining visible lesion (i.e., not in an area of tissue appearing grossly normal after a clinical response) might reveal no histologic change.
The role of tobacco in carcinogenesis in aerodigestive tract epithelia is beyond dispute6,27. The impact of tobacco on the subsequent natural history of leukoplakia or the development of a second primary tumor (the leading cause of death, after early head-and-neck cancer28-30) is less clear2,3,5,8,11. Our previous studies10,11 and our present trial found no significant effect of smoking or its cessation on the end points of oral premalignant lesions or second primary tumors.
Recent data suggest that the biologic effects of retinoids are mediated by retinoic acid nuclear receptors. The sequencing of these receptors in the DNA-binding region indicates that they are members of the steroid-receptor superfamily31-34. It is known that isotretinoin can easily be isomerized to all-trans-retinoic acid, which is the known ligand for retinoic acid nuclear receptors. On the other hand, beta carotene is far removed from and not easily metabolized into all-trans-retinoic acid. This difference between the two agents may contribute to differences in their chemopreventive activity. Recent data suggest that retinoic acid receptors mediate the biologic effects of retinoids, specifically in human oral leukoplakia35.
Supported by a Public Health Service grant (CA-46303) from the National Cancer Institute. Dr. Lippman is the recipient of a Clinical Oncology Career Development Award from the American Cancer Society.
We are indebted to Dr. Adel El-Naggar for his histologic review; to Becky Gossett, Rosanne Trost, and Karen McCarthy for their clinical assistance; to Charles Earley for technical assistance; and to Stephanie Johnson and Sarita Jackson for their assistance in 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.
- References
References
1
Kramer IR ,Lucas RB ,Pindborg JJ ,Sobin LH . Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978;46:518-539
CrossRef | Medline2
Silverman S Jr, ed. Oral cancer. 3rd ed. Atlanta: American Cancer Society, 1990.
3
Silverman S Jr ,Gorsky M ,Lozada F . Oral leukoplakia and malignant transformation: a follow-up study of 257 patients. Cancer 1984;53:563-568
CrossRef | Web of Science | Medline4
Slaughter DP ,Southwick HW ,Smejkal W . Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 1953;6:963-968
CrossRef | Web of Science | Medline5
Lippman SM ,Hong WK . Second malignant tumors in head and neck squamous cell carcinoma: the overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys 1989;17:691-694
CrossRef | Web of Science | Medline6
Wolf G, Lippman SM, Laramore G, Hong WK. Head and neck cancer. In: Holland JF, Frei E, Bast RC Jr, Kufe DW, Morton DL, Weichselbaum R, eds. Cancer medicine. 3rd ed. Philadelphia: Lea & Febiger, 1992:1211-74.
7
Sporn MB . Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976;36:2699-2702
Web of Science | Medline8
Lippman SM, Hong WK. Retinoid chemoprevention of upper aerodigestive tract carcinogenesis. In: DeVita VT, Hellman S, Rosenberg SA, eds. Important advances in oncology 1992. Philadelphia: J.B. Lippincott, 1992:93-109.
9
Shin DM ,Gimenez IB ,Lee JS , et al. Expression of epidermal growth factor receptor, polyamine levels, ornithine decarboxylase activity, micronuclei, and transglutaminase I in a 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model. Cancer Res 1990;50:2505-2510
Web of Science | Medline10
Hong WK ,Endicott J ,Itri LM , et al. 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986;315:1501-1505
Full Text | Web of Science | Medline11
Hong WK ,Lippman SM ,Itri LM , et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 1990;323:795-801
Full Text | Web of Science | Medline12
Sporn MB ,Dunlop NM ,Newton DL ,Smith JM . Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976;35:1332-1338
Medline13
Lotan R . Effects of vitamin A and its analogs (retinoids) on normal and neoplastic cells. Biochim Biophys Acta 1980;605:33-91
Web of Science | Medline14
Bollag W . Vitamin A and retinoids: from nutrition to pharmacotherapy in dermatology and oncology. Lancet 1983;1:860-863
CrossRef | Web of Science | Medline15
Lippman SM ,Kessler JF ,Meyskens FL Jr . Retinoids as preventive and therapeutic anticancer agents. Cancer Treat Rep 1987;71:391-405, 493
Medline16
Band PR ,Feldstein M ,Saccomanno G . Reversibility of bronchial marked atypia: implication for chemoprevention. Cancer Detect Prev 1986;9:157-160
Web of Science | Medline17
Kraemer KH ,DiGiovanna JJ ,Moshell AN ,Tarone RE ,Peck GL . Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med 1988;318:1633-1637
Full Text | Web of Science | Medline18
Peto R ,Doll R ,Buckley JD ,Sporn MB . Can dietary beta-carotene materially reduce human cancer rates? Nature 1981;290:201-208
CrossRef | Web of Science | Medline19
Winn DM ,Ziegler RG ,Pickle LW ,Gridley G ,Blot WJ ,Hoover RN . Diet in the etiology of oral and pharyngeal cancer among women from the southern United States. Cancer Res 1984;44:1216-1222
Web of Science | Medline20
Greenberg ER ,Baron JA ,Stukel TA , et al. A clinical trial of beta carotene to prevent basal-cell and squamous-cell cancers of the skin. N Engl J Med 1990;323:789-795
Full Text | Web of Science | Medline21
Ajani JA ,Welch SR ,Raber MN ,Fields WS ,Krakoff IH . Comprehensive criteria for assessing therapy-induced toxicity. Cancer Invest 1990;8:147-159
CrossRef | Web of Science | Medline22
Meyskens FL Jr ,Goodman GE ,Alberts DS . 13-Cis-retinoic acid: pharmacology, toxicology, and clinical applications for the prevention and treatment of human cancer. Crit Rev Oncol Hematol 1985;3:75-101
CrossRef | Web of Science | Medline23
Woolson RF. Statistical methods for the analysis of biomedical data. New York: John Wiley, 1987.
24
Lippman SM ,Lee JS ,Lotan R ,Hittelman W ,Wargovich MJ ,Hong WK . Biomarkers as intermediate end points in chemoprevention trials. J Natl Cancer Inst 1990;82:555-560
CrossRef | Web of Science | Medline25
Batsakis JG, ed. Tumors of the head and neck: clinical and pathological considerations. 2nd ed. Baltimore: Williams & Wilkins, 1979.
26
Hyams VJ, Batsakis JG, Michaels L, eds. Tumors of the upper respiratory tract and ear. Atlas of tumor pathology. 2nd series. Fascicle 25. Washington, D.C.: Armed Forces Institute of Pathology, 1988.
27
Decker J ,Goldstein JC . Current concepts in otolaryngology: risk factors in head and neck cancer. N Engl J Med 1982;306:1151-1155
Full Text | Web of Science | Medline28
Cooper JS ,Pajak TF ,Rubin P , et al. Second malignancies in patients who have head and neck cancer: incidence, effect on survival and implications based on the RTOG experience. Int J Radiat Oncol Biol Phys 1989;17:449-456
CrossRef | Web of Science | Medline29
Tepperman BS ,Fitzpatrick PJ . Second respiratory and upper digestive tract cancers after oral cancer. Lancet 1981;2:547-549
CrossRef | Web of Science | Medline30
Vikram B . Changing patterns of failure in advanced head and neck cancer. Arch Otolaryngol 1984;110:564-565
Web of Science | Medline31
Evans RM . The steroid and thyroid hormone receptor superfamily. Science 1988;240:889-895
CrossRef | Web of Science | Medline32
Gudas LJ . Molecular mechanisms of retinoid action. Am J Respir Cell Mol Biol 1990;2:319-320
Web of Science | Medline33
Lotan R ,Clifford JL . Nuclear receptors for retinoids: mediators of retinoid effects on normal and malignant cells. Biomed Pharmacother 1991;45:145-156
CrossRef | Web of Science | Medline34
Smith MA ,Parkinson DR ,Cheson BD ,Friedman MA . Retinoids in cancer therapy. J Clin Oncol 1992;10:839-864
Web of Science | Medline35
Hu L ,Crowe DL ,Rheinwald JG ,Chambon P ,Gudas LJ . Abnormal expression of retinoic acid receptors and keratin 19 by human oral and epidermal squamous cell carcinoma cell lines. Cancer Res 1991;51:3972-3981
Web of Science | Medline
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Scott M. Lippman, J. Jack Lee. 2008. Cancer Chemoprevention. , 711-720.
CrossRef16
Célia Luiza Petersen Vitello Kalil, Fernanda Zatti Fachinello, Flávia Maria Lamb, Luciane Nardi Comunello. (2008) Use of Oral Isotretinoin in Photoaging Therapy. SKINmed 7:1, 10-14
CrossRef17
Anthonise Louis Fields, Dianne Robert Soprano, Kenneth J. Soprano. (2007) Retinoids in biological control and cancer. Journal of Cellular Biochemistry 102:4, 886-898
CrossRef18
Richard M NILES. (2007) Biomarker and animal models for assessment of retinoid efficacy in cancer chemoprevention. Acta Pharmacologica Sinica 28:9, 1383-1391
CrossRef19
Xiao-Chun Xu. (2007) Tumor-suppressive activity of retinoic acid receptor-β in cancer. Cancer Letters 253:1, 14-24
CrossRef20
John M Wrangle, Fadlo R Khuri. (2007) Chemoprevention of squamous cell carcinoma of the head and neck. Current Opinion in Oncology 19:3, 180-187
CrossRef21
Susan R. Mallery, Gary D. Stoner, Peter E. Larsen, Henry W. Fields, Kapila A. Rodrigo, Steven J. Schwartz, Qingguo Tian, Jin Dai, Russell J. Mumper. (2007) Formulation and In-Vitro and In-Vivo Evaluation of a Mucoadhesive Gel Containing Freeze Dried Black Raspberries: Implications for Oral Cancer Chemoprevention. Pharmaceutical Research 24:4, 728-737
CrossRef22
Giovanni Lodi, Andrea Sardella, Cristina Bez, Federica Demarosi, Antonio Carrassi, Giovanni Lodi. 2006. Interventions for treating oral leukoplakia. .
CrossRef23
Virendra N. Sehgal, Govind Srivastava, Kabir Sardana. (2006) Isotretinoin - unapproved indications/uses and dosage: a physician's reference. International Journal of Dermatology 45:6, 772-777
CrossRef24
Christiane Querfeld, Lakshmi V Nagelli, Steven T Rosen, Timothy M Kuzel,, Joan Guitart. (2006) Bexarotene in the treatment of cutaneous T-cell lymphoma. Expert Opinion on Pharmacotherapy 7:7, 907-915
CrossRef25
Ann Gillenwater, Vali Papadimitrakopoulou, Rebecca Richards-Kortum. (2006) Oral premalignancy: New methods of detection and treatment. Current Oncology Reports 8:2, 146-154
CrossRef26
Ranju Ralhan, Nitin Chakravarti, Jatinder Kaur, Chavvi Sharma, Anupam Kumar, Meera Mathur, Sudhir Bahadur, Nootan Kumar Shukla, Suryanaryana VS Deo. (2006) Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: Relationship with cell cycle regulators. International Journal of Cancer 118:5, 1077-1089
CrossRef27
Wade Smith, Nabil Saba. (2005) Retinoids as chemoprevention for head and neck cancer: where do we go from here?. Critical Reviews in Oncology/Hematology 55:2, 143-152
CrossRef28
Fernando Arias Vega, Miguel Angel Domínguez Domínguez, Ana Manterola Burgaleta, Ruth Vera García, Maria Eugenia Echeverría Zabalza, Eugenio Oria Mundin, Enrique Martínez López, Pilar Romero Rojano, Elena Villafranca Iture. (2005) Concomitant boost radiation and concurrent cisplatin for advanced head and neck carcinomas. Preliminary results of a phase II, single-institutional trial. Clinical and Translational Oncology 7:2, 60-65
CrossRef29
Wen-Chuan Wu, Dan-Ning Hu, Sneha Mehta, Yo-Chen Chang. (2005) Effects of Retinoic Acid on Retinal Pigment Epithelium from Excised Membranes from Proliferative Vitreoretinopathy. Journal of Ocular Pharmacology and Therapeutics 21:1, 44-54
CrossRef30
Richard M. Niles. (2004) Signaling pathways in retinoid chemoprevention and treatment of cancer. Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 555:1-2, 97-105
CrossRef31
Sanjay Jain, Fadlo R. Khuri, Dong M. Shin. (2004) Prevention of head and neck cancer: Current status and future prospects. Current Problems in Cancer 28:5, 265-286
CrossRef32
Nabil Saba, Sanjay Jain, Fadlo Khuri. (2004) Chemoprevention in lung cancer. Current Problems in Cancer 28:5, 287-306
CrossRef33
G Lodi, A Sardella, C Bez, F Demarosi, A Carrassi, Giovanni Lodi. 2004. Interventions for treating oral leukoplakia. .
CrossRef34
M.R. Forman, S.D. Hursting, A. Umar, J.C. Barrett. (2004) NUTRITION AND CANCER PREVENTION: A Multidisciplinary Perspective on Human Trials*. Annual Review of Nutrition 24:1, 223-254
CrossRef35
John C Rhee, Fadlo R Khuri, Dong M Shin. (2004) Emerging drugs for head and neck cancer. Expert Opinion on Emerging Drugs 9:1, 91-104
CrossRef36
Fernando Arias de la Vega, R. Vera Garc??a, Dom??nguez Dom??nguez, E. Villafranca Iturre, E. Mart??nez L??pez, S. Miquelez Alonso, P. Romero, J. Medina Sola. (2003) Hyperfractionated Radiotherapy and Concomitant Cisplatin for Locally Advanced Laryngeal and Hypopharyngeal Carcinomas. American Journal of Clinical Oncology 26:6, 550-557
CrossRef37
Jean-Charles Soria, Edward S Kim, Jéôme Fayette, Sylvie Lantuejoul, Eric Deutsch, Waun Ki Hong. (2003) Chemoprevention of lung cancer. The Lancet Oncology 4:11, 659-669
CrossRef38
William B. Armstrong, X. Steven Wan, Ann R. Kennedy, Thomas H. Taylor, Frank L. Meyskens. (2003) Development of the Bowman-Birk inhibitor for oral cancer chemoprevention and analysis of neu immunohistochemical staining intensity with Bowman-Birk inhibitor concentrate treatment. The Laryngoscope 113:10, 1687-1702
CrossRef39
Lori J Wirth, Robert I Haddad, Marshall R Posner. (2003) Progress and perspectives in chemoprevention of head and neck cancer. Expert Review of Anticancer Therapy 3:3, 339-355
CrossRef40
Katrina Y. Glover, Vali A. Papadimitrakopoulou. (2003) Chemoprevention of head and neck cancer. Current Oncology Reports 5:2, 152-157
CrossRef41
Waun Ki Hong. (2003) General Keynote: The Impact of Cancer Chemoprevention. Gynecologic Oncology 88:1, S56-S58
CrossRef42
Eric C. Dietze, L. Elizabeth Caldwell, Kelly Marcom, Steven J. Collins, Lisa Yee, Karen Swisshelm, Katherine B. Hobbs, Gregory R. Bean, Victoria L. Seewaldt. (2002) Retinoids and retinoic acid receptors regulate growth arrest and apoptosis in human mammary epithelial cells and modulate expression of CBP/p300. Microscopy Research and Technique 59:1, 23-40
CrossRef43
Meir Gorsky, Joel B. Epstein. (2002) The effect of retinoids on premalignant oral lesions. Cancer 95:6, 1258-1264
CrossRef44
I Klaassen. (2002) Anticancer activity and mechanism of action of retinoids in oral and pharyngeal cancer. Oral Oncology 38:6, 532-542
CrossRef45
Edward S. Kim, Fadlo R. Khuri. (2002) Chemoprevention of lung cancer. Current Oncology Reports 4:4, 341-346
CrossRef46
Elin Albrechtsson, Bodil Ohlsson, Jan Axelson. (2002) The Expression of Retinoic Acid Receptors and the Effects in Vitro by Retinoids in Human Pancreatic Cancer Cell Lines. Pancreas 25:1, 49-56
CrossRef47
Edward S. Kim, Waun Ki Hong, Fadlo Raja Khuri. (2002) C
HEMOPREVENTION OF AERODIGESTIVE TRACT CANCERS . Annual Review of Medicine 53:1, 223-243
CrossRef48
Sundar Santhanam, Marios Decatris, Ken O??Byrne. (2002) Potential of Interferon-?? in Solid Tumours. BioDrugs 16:5, 349-372
CrossRef49
Stacy L. McClure, Jayme Valentine, Kenneth B. Gordon. (2002) Comparative Tolerability of Systemic Treatments for Plaque-Type Psoriasis. Drug Safety 25:13, 913-927
CrossRef50
Shi-Yong Sun, Reuben Lotan. (2002) Retinoids and their receptors in cancer development and chemoprevention. Critical Reviews in Oncology/Hematology 41:1, 41-55
CrossRef51
Cherie-Ann O. Nathan, Igor L. Leskov, Meihong Lin, Fleurette W. Abreo, Runhua Shi, Golda H. Hartman, Jonathan Glass. (2001) COX-2 expression in dysplasia of the head and neck. Cancer 92:7, 1888-1895
CrossRef52
S. M. Lippman, J. J. Lee, D. D. Karp, E. E. Vokes, S. E. Benner, G. E. Goodman, F. R. Khuri, R. Marks, R. J. Winn, W. Fry, S. L. Graziano, D. R. Gandara, G. Okawara, C. L. Woodhouse, B. Williams, C. Perez, H. W. Kim, R. Lotan, J. A. Roth, W. K. Hong. (2001) Randomized Phase III Intergroup Trial of Isotretinoin to Prevent Second Primary Tumors in Stage I Non-Small-Cell Lung Cancer. JNCI Journal of the National Cancer Institute 93:8, 605-618
CrossRef53
CHANGPING ZOU, MONICA LIEBERT, CHANGCHUN ZOU, H. BARTON GROSSMAN, REUBEN LOTAN. (2001) IDENTIFICATION OF EFFECTIVE RETINOIDS FOR INHIBITING GROWTH AND INDUCING APOPTOSIS IN BLADDER CANCER CELLS. The Journal of Urology 165:3, 986-992
CrossRef54
CHANGPING ZOU, MONICA LIEBERT, CHANGCHUN ZOU, H. BARTON GROSSMAN, REUBEN LOTAN. (2001) IDENTIFICATION OF EFFECTIVE RETINOIDS FOR INHIBITING GROWTH AND INDUCING APOPTOSIS IN BLADDER CANCER CELLS. The Journal of Urology986-992
CrossRef55
Vali A. Papadimitrakopoulou, Waun K. Hong. (2000) Biomolecular markers as intermediate end points in chemoprevention trials of upper aerodigestive tract cancer. International Journal of Cancer 88:6, 852-855
CrossRef56
Richard M Niles. (2000) Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition 16:11-12, 1084-1089
CrossRef57
Dongmei Zhang, William F. Holmes, Shujian Wu, Dianne R. Soprano, Kenneth J. Soprano. (2000) Retinoids and ovarian cancer. Journal of Cellular Physiology 185:1, 1-20
CrossRef58
Ernest T. Hawk, Scott M. Lippman. (2000) PRIMARY CANCER PREVENTION TRIALS. Hematology/Oncology Clinics of North America 14:4, 809-830
CrossRef59
Richard M Niles. (2000) Vitamin A and cancer. Nutrition 16:7-8, 573-576
CrossRef60
Vali A. Papadimitrakopoulou. (2000) Carcinogenesis of head and neck cancer and the role of chemoprevention in its reversal. Current Opinion in Oncology 12:3, 240-245
CrossRef61
Claudio Botti, Barbara Pescatore, Marcella Mottolese, Francesco Sciarretta, Claudia Greco, Franco Di Filippo, Giuseppe Maria Gandolfo, Francesco Cavaliere, Roberta Bovani, Antonio Varanese, Anna Maria Cianciulli. (2000) Incidence of chromosomes 1 and 17 aneusomy in breast cancer and adjacent tissue: an interphase cytogenetic study11No competing interests declared.. Journal of the American College of Surgeons 190:5, 530-539
CrossRef62
Fadlo R. Khuri, Scott M. Lippman. (2000) Lung cancer chemoprevention. Seminars in Surgical Oncology 18:2, 100-105
CrossRef63
Frank L. Meyskens. (2000) Criteria for implementation of large and multiagent clinical chemoprevention trials. Journal of Cellular Biochemistry 77:S34, 115-120
CrossRef64
Michael Reiss. (1999) TGF-β and cancer. Microbes and Infection 1:15, 1327-1347
CrossRef65
S. M. Lippman, P. H. Brown. (1999) Tamoxifen Prevention of Breast Cancer: an Instance of the Fingerpost. JNCI Journal of the National Cancer Institute 91:21, 1809-1819
CrossRef66
Joel B. Epstein, Meir Gorsky. (1999) Topical application of vitamin A to oral leukoplakia. Cancer 86:6, 921-927
CrossRef67
M Copper. (1999) Plasma retinoid levels in head and neck cancer patients: a comparison with healthy controls and the effect of retinyl palmitate treatment. Oral Oncology 35:1, 40-44
CrossRef68
John D. Radcliffe, Victorine L. Imrhan, Andie M. Hsueh. (1998) The Use of Soy Protein Isolate to Reduce the Severity of 13-cis Retinoic Acid-Induced Hypertriglyceridemia. Cancer Detection <html_ent glyph="@amp;" ascii="&"/> Prevention 22:6, 526-532
CrossRef69
Donald D. Hensrud, Douglas C. Heimburger. (1998) DIET, NUTRIENTS, AND GASTROINTESTINAL CANCER. Gastroenterology Clinics of North America 27:2, 325-346
CrossRef70
K Liede, J Hietanen, L Saxen, J Haukka, T Timonen, R Hayrinen-Immonen, OP Heinonen. (1998) Long-term supplementation with alpha-tocopherol and beta-carotene and prevalence of oral mucosal lesions in smokers. Oral Diseases 4:2, 78-83
CrossRef71
Scott M. Lippman, Steven E. Benner, Herbert A. Fritsche, Jr., Jin Soo Lee, Waun Ki Hong. (1998) The Effect of 13-cis-Retinoic Acid Chemoprevention on Human Serum Retinol Levels. Cancer Detection <html_ent glyph="@amp;" ascii="&"/> Prevention 22:1, 51-56
CrossRef72
G Shklar. (1998) Mechanisms of cancer inhibition by anti-oxidant nutrients. Oral Oncology 34:1, 24-29
CrossRef73
Michael A. Zasloff, David M. Rocke, Leslie J. Crofford, Gregory V. Hahn, Frederick S. Kaplan. (1998) Treatment of Patients Who Have Fibrodysplasia Ossificans Progressiva With Isotretinoin. Clinical Orthopaedics and Related Research 346, 121???129
CrossRef74
N. Tradati, R. Grigolat, L. Calabrese, L. Costa, G. Giugliano, F. Morelli, C. Scully, P. Boyle, F. Chiesa. (1997) Oral leukoplakias: to treat or not?. Oral Oncology 33:5, 317-321
CrossRef75
I. van der Waal, K.P. Schepman, E.H. van der Meij, L.E. Smeele. (1997) Oral leukoplakia: a Clinicopathological review. Oral Oncology 33:5, 291-301
CrossRef76
John D. Potter. (1997) β-Carotene and the role of intervention studies. Cancer Letters 114:1-2, 329-331
CrossRef77
Matthew T. Speyer, Jon A. Jackson, Brian B. Burkey. (1997) The Effects of 13- cis Retinoic Acid on Squamous Cell Carcinoma Proliferation and Adhesion to Extracellular Matrix Proteins. The Laryngoscope 107:1, 44-48
CrossRef78
W. J. Issing, R. Struck, A. Naumann. (1997) Positive impact of retinyl palmitate in leukoplakia of the larynx. European Archives of Oto-Rhino-Laryngology 254:S1, S105-S109
CrossRef79
Susan A. Eicher, Reuben Lotan. (1996) Differential Effects of Retinoic Acid and N-(4-hydroxyphenyl)retinamide on Head and Neck Squamous Cell Carcinoma Cells. The Laryngoscope 106:12, 1471-1475
CrossRef80
R. Jyothirmayi, K. Ramadas, C. Varghese, R. Jacob, M.K. Nair, R. Sankaranarayanan. (1996) Efficacy of vitamin A in the prevention of loco-regional recurrence and second primaries in head and neck cancer. European Journal of Cancer. Part B: Oral Oncology 32:6, 373-376
CrossRef81
Wolfgang J. Issing, Rainer Struck, Andreas Naumann. (1996) Long-term follow-up of larynx leukoplakia under treatment with retinyl palmitate. Head & Neck 18:6, 560-565
CrossRef82
Dae Ghon Kim, Baik Hwan Jo, Kyung Ran You, Deuk Soo Ahn. (1996) Apoptosis induced by retinoic acid in Hep 3B cells in vitro. Cancer Letters 107:1, 149-159
CrossRef83
Philip A. Swango. (1996) Cancers of the Oral Cavity and Pharynx in the United States: An Epidemiologic Overview. Journal of Public Health Dentistry 56:6, 309-318
CrossRef84
Li Mao, Jin S. Lee, You H. Fan, Jae Y. Ro, John G. Batsakis, Scott Lippman, Walter Hittelman, Waun K. Hong. (1996) Frequent microsatellite alterations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk assessment. Nature Medicine 2:6, 682-685
CrossRef85
Pablo M. Gonzalez, Steven E. Benner. (1996) Clinical studies in head and neck cancer chemoprevention. Cancer and Metastasis Review 15:1, 113-118
CrossRef86
Vali A. Papadimitrakopoulou, Dong M. Shin, Waun K. Hong. (1996) Molecular and cellular biomarkers for field cancerization and multistep process in head and neck tumorigenesis. Cancer and Metastasis Review 15:1, 53-76
CrossRef87
(1996) Clinical development plan: 13-cis-Retinoic acid. Journal of Cellular Biochemistry 63:S26, 168-201
CrossRef88
Walter N. Hittelman, Hyo J. Kim, Jin S. Lee, Dong M. Shin, Scott M. Lippman, Jin Kim, Jae Y. Ro, Waun Ki Hong. (1996) Detection of chromosome instability of tissue fields at risk: In situ hybridization. Journal of Cellular Biochemistry 63:S25, 57-62
CrossRef89
Lotan, Reuben, Xu, Xiao-Chun, Lippman, Scott M., Ro, Jae Y., Lee, Jin S., Lee, J. Jack, Hong, Waun K., . (1995) Suppression of Retinoic Acid Receptor–β in Premalignant Oral Lesions and Its Up-Regulation by Isotretinoin. New England Journal of Medicine 332:21, 1405-1411
Full Text90
P. Boyle, G.J. Macfarlane, W.J. Blot, F. Chiesa, J.L. Lefebvre, A.Mano Azul, N. de Vries, C. Scully. (1995) European school of oncology advisory report to the European Commission for the Europe against cancer programme: Oral carcinogenesis in Europe. European Journal of Cancer. Part B: Oral Oncology 31:2, 75-85
CrossRef91
Scott M. Lippman, Richard A. Heyman, Jonathan M. Kurie, Steven E. Benner, Waun Ki Hong. (1995) Retinoids and chemoprevention: Clinical and basic studies. Journal of Cellular Biochemistry 59:S22, 1-10
CrossRef92
Babu Mathew, Rengaswamy Sankaranarayanan, Padmanabhan P. Nair, Cherian Varghese, Thara Somanathan, B. Padmavathy Amma, N. Sreedevi Amma, Madhavan Krishnan Nair. (1995) Evaluation of chemoprevention of oral cancer with spirulina fusiformis. Nutrition and Cancer 24:2, 197-202
CrossRef93
Steven E. Benner, Scott M. Lippman, Michael J. Wargovich, J. Jack Lee, Marco Velasco, Jack W. Martin, Bela B. Toth, Waun K. Hong. (1994) Micronuclei, a biomarker for chemoprevention trials: Results of a randomized study in oral pre-malignancy. International Journal of Cancer 59:4, 457-459
CrossRef94
Daniel W. Nixon. (1994) Special aspects of cancer prevention trials. Cancer 74:S9, 2683-2686
CrossRef95
Steven E. Benner, Scott M. Lippman, Waun Ki Hong. (1994) Retinoid lung cancer prevention. Lung Cancer 11, S71-S78
CrossRef96
Scott M. Lippman, Margaret Spitz, Zoltan Trizna, Steven E. Benner, Waun Ki Hong. (1994) Epidemiology, biology, and chemoprevention of aerodigestive cancer. Cancer 74:S9, 2719-2725
CrossRef97
Martin H. Huber, Waun Ki Hong. (1994) Biology and chemoprevention of head and neck cancer. Current Problems in Cancer 18:2, 86-140
CrossRef98
Jonathan M. Kurie, Scott M. Lippman, Waun Ki Hong. (1994) Potential of retinoids in cancer prevention. Cancer Treatment Reviews 20:1, 1-10
CrossRef99
(1994) Clinical development plan: β-Carotene and other carotenoids. Journal of Cellular Biochemistry 56:S20, 110-140
CrossRef100
Christine E. Szarka, Generosa Grana, Paul F. Engstrom. (1994) Chemoprevention of cancer. Current Problems in Cancer 18:1, 6-79
CrossRef101
Loretta M. Itri. (1993) Cancer chemoprevention. Cancer 72:S11, 3374-3380
CrossRef102
Peter Boyle, GaryJ. Macfarlane, Crispian Scully. (1993) Oral cancer: necessity for prevention strategies. The Lancet 342:8880, 1129
CrossRef103
H. B. St
helin. (1993) Critical reappraisal of vitamins and trace minerals in nutritional support of cancer patients. Supportive Care in Cancer 1:6, 295-297
CrossRef104
Scott M. Lippman, Steven E. Benner, Waun Ki Hong. (1993) Chemoprevention strategies for the control of cancer. Cancer 72:S3, 984-990
CrossRef105
Vokes, Everett E.Weichselbaum, Ralph R.Lippman, Scott M.Hong, Waun Ki. (1993) Head and Neck Cancer. New England Journal of Medicine 328:3, 184-194
Full Text106
Richtsmeier, William J., . (1993) Biologic Modifiers and Chemoprevention of Cancer of the Oral Cavity. New England Journal of Medicine 328:1, 58-59
Full Text107
Stimson P. Schantz. (1993) Chemoprevention strategies: The relevance of premalignant and malignant lesions of the upper aerodigestive tract. Journal of Cellular Biochemistry 53:S17F, 18-26
CrossRef
