Cancer chemoprevention is defined as the use of
chemical agents to suppress or reverse carcinogenesis to prevent the
development of invasive cancer.[1,2] Two basic concepts underlie this
approach to cancer control: the multistep nature of cancer
development and field carcinogenesis.
The development of cancer occurs over years and involves multiple
genetic and phenotypic alterations that lead to invasive cancer.
Chemoprevention is based on the premise that intervention is possible
during the many steps of this process.
Based on animal model studies, carcinogenesis has been broadly
divided into three phases: initiation, promotion, and progression. In
initiation, a carcinogen interacts with DNA, producing a fixed
mutation. The specific molecular change depends on the carcinogen and
can be influenced by a number of factors, including the rate and type
of carcinogenic metabolism and the response of the DNA repair function.
During promotion, the initiated cells proliferate. This stage occurs
over a long period and can be altered by agents that affect growth rates.
Progression is the phase between a premalignant lesion and the
development of invasive cancer. During this stage, genetic and
phenotypic changes occur, with the rate of progression based on the
rate of genetic mutation and cell proliferation.[1-8] Studies of
molecular progression in colon cancer support this model of
carcinogenesis, which involves a series of acquired genetic changes.
Field carcinogenesis is the concept that, in patients at risk,
extensive, multifocal, genetically distinct premalignant and
malignant lesions can occur within the whole carcinogen-exposed
region. The classic example is exposure of the upper aerodigestive
tract and lungs to the carcinogenic effects of tobacco. The
finding of one neoplasm in the exposed area provides evidence for the
presence of multiple premalignant lesions of independent origin.
In this setting, lesion-specific therapy is insufficient;
interventions that prevent the promotion and progression of
unrecognized lesions are needed.
Chemopreventive strategies can be applied to the general population
or to high-risk groups.[11-13] For use as a chemopreventive agent
among the general population, a compound must have minimal or no
toxicity. Agents that show promise for this purpose include dietary
constituents or their analogs, as well as medicinals, such as
nonsteroidal anti-inflammatory drugs (NSAIDs).[11-13]
High-risk individuals include those who have a genetic predisposition
to cancer, prior cancer diagnosis, history of a significant exposure
to a carcinogen, or a histology that indicates an elevated likelihood
of developing cancer. Because of their increased risk, some toxicity
may be acceptable in these populations.
In addition, subjects at high risk are ideal subjects for clinical
trials of chemopreventive agents because their increased incidence
rates allow for smaller study sample sizes.[11,14,15] For example,
selection of participants for studies of breast cancer
chemoprevention generally relies on the identification of high-risk
proliferative breast histology or epidemiologic factors known to
increase a womans risk of developing breast cancer. In general,
women with a ³ 20% lifetime risk of
developing breast cancer are considered to be good candidates for
participation in chemoprevention trials.
Chemoprevention trials administer specific natural or synthetic
substances with the objective of reversing, suppressing, or
preventing carcinogenic progression to invasive cancers. In
preclinical research, the efficacy and toxicity of a chemopreventive
agent are assessed via in vitro cell screening systems and in vivo
assays using animal models.[11-15]
Designs for phase I-III chemoprevention trials are based on similar
principles as chemotherapeutic trials. A number of issues unique to
chemoprevention exist, however. Whereas phase I chemotherapy trials
identify maximum tolerable doses in patients with refractory cancer,
phase I chemoprevention trials establish safe doses with minimal
toxicity for relatively healthy subjects.[11,14,15]
Study End Points: Surrogate End Point Biomarkers
After establishing the dose level with the optimal chemopreventive
toxicity profile, phase II clinical trials evaluate biological
efficacy in a larger group of patients at high risk for specific
cancers and provide data that characterize dose, safety, and toxicity
in the selected population. The primary end points of phase II trials
are biological indices of neoplasia, based on clinical, histologic,
genetic, biochemical, proliferative, or differentiation-related
properties, that can be used to estimate the potential for neoplastic
progression to cancer and to determine the effect of the
chemopreventive agent being tested on these indices.[11,14,15] These
biological indices are referred to as surrogate, or intermediate, end
Phase IIa trials are feasibility studies of surrogate end point
biomarkers and can include dose de-escalation studies to determine
the lowest, least toxic drug dose that retains biological activity.
In phase IIb trials, preliminary surrogate end point biomarkers are
confirmed by definitive randomized study of treatment and control arms.
After short-term activity is established, phase III trials are
conducted to establish long-term efficacy in reducing cancer
incidence. Phase III trials can require thousands of subjects and 5
to 10 years to complete. Innovative strategies, such as factorial
designs and the use of a vanguard cohort, have been developed to
maximize the use of limited resources.[11,14,15]
Cancer incidence is the obvious end point of a trial investigating a
chemopreventive agent. The low incidence of cancer, however, even in
high-risk populations, necessitates lengthy studies with thousands of
patients, entailing tremendous expense.
Identification and validation of surrogate end point biomarkers is
vital to prevention research; eventually, surrogate biomarkers may
replace cancer incidence as end points in large-scale clinical
trials. With the development of valid surrogate end point biomarkers,
fewer subjects will be required for the study to achieve the desired
level of statistical power, and interventions can be evaluated over a
shorter period than is possible when cancer is used as the end point.[11,14,15]
Characteristics of the Ideal Surrogate Biomarker--A valid
surrogate biomarker should be on the causal pathway of cancer, and
not simply an associated change. It should be expressed differently
in normal than in high-risk premalignant sites; change its pattern
and/or degree of expression in correlation with the stage of
carcinogenesis; have a low rate of spontaneous change; and be
technically and logistically feasible to measure.[11,14]
It should be possible to modulate a surrogate end point biomarker by
chem-opreventive agents in such as way as to lead to a decrease in
the incidence of cancer. Thus, surrogate end point biomarkers differ
from susceptibility markers, such as certain genetic polymorphisms
and mutagen sensitivity. Finally, surrogate biomarkers should have
known sensitivity, specificity, and positive predictive value for the
development of cancer.[11,14,16]
The best-studied biomarkers are nonspecific indicators of
genotoxicity and cell proliferation. Types of biomarkers include
clinical and histologic parameters, genetic markers, proliferation
markers, biochemical indicators, and differentiation markers.[4-6,11,14-17]
Surrogate End Point Biomarkers Under Study--Surrogate end
point biomarkers can include markers of certain site-specific
changes, such as the premalignant lesions listed below, or markers of
general cellular/molecular changes, such as altered differentiation
and proliferation, that can occur at many sites. Site-specific
surrogate end point biomarkers (premalignant changes) currently under
study include ductal carcinoma in situ (breast), prostatic
intraepithelial neoplasia (prostate), adenomas and aberrant crypts
(colon), papillomas (bladder), cervical intraepithelial neoplasia and
human papillomavirus (HPV; cervix), leukoplakia (oral cavity), and
squamous metaplasia (eg, larynx and lung). DNA ploidy, growth factor
receptors (eg, epidermal growth factor receptor [EGFR]), oncogene
expression, loss of heterozygosity, quantitative morphometric
features, and proliferation, differentiation, and apoptosis markers
are examples of general surrogate biomarkers (biomarkers of
cellular/molecular changes) currently under study.[11,14,16,17]
1. Lotan R: Retinoids in cancer chemoprevention. FASEB J
2. Mavne ST, Lippman SM: Retinoids and carotenoids, in DeVita VT,
Hellman S, Rosenberg SA (eds): Cancer Principles & Practice of
Oncology, 5th ed, pp 585-599. Philadelphia, Lippincott-Raven, 1997.
3. Meyskens FL: Cancer prevention: Diet and risk reduction, in DeVita
VT, Hellman S, Rosenberg SA (eds): Cancer Principles & Practice
of Oncology, 5th ed, pp 573-579. Philadelphia, Lippincott-Raven, 1997.
4. Sporn MB, Dunlop NM, Newton DL, et al: Prevention of chemical
carcinogenesis by vitamin A and its synthetic analogs. Fed Proc
5. Sporn MB: Chemoprevention of cancer. Lancet 342:1211-1213, 1993.
6. Bertram JS, Kolonel LN, Meyskens FL: Rationale and strategies for
chemoprevention of cancer in humans. Cancer Res 47:3012-3031, 1987.
7. Slaga TJ: Cellular and molecular mechanisms involved in multistage
skin carcinogenesis. Carcinog Compr Surv 11:1-18, 1989.
8. DiGiovanni J: Inhibition of chemical carcinogenesis, in Cooper CS,
Grover PL (eds): Chemical Carcinogenesis and Mutagenesis II, pp
159-224. Berlin, Springer-Verlag, 1990.
9. Vogelstein B, Fearon ER, Hamilton SR: Genetic alterations during
colorectal tumor development. N Engl J Med 319:525-532, 1988.
10. Mao L, Lee JS, Kurie JM, et al: Clonal genetic alterations in the
lungs of current and former smokers. J Natl Cancer Inst
11. Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin
Oncol 12:851-873, 1994.
12. Wattenberg LW: Chemoprevention of cancer. Prev Med 25:44-45, 1996.
13. Wattenberg LW: Prevention, therapy, and basic science and the
resolution of the cancer problem. Cancer Res 53:5890-5896, 1993.
14. Lippman SM, Lee JS, Lotan R, et al: Biomarkers as intermediate
endpoints in chemoprevention trials. J Natl Cancer Inst 82:555-560, 1990.
15. Greenwald P: Preventive clinical trials. Ann N Y Acad Sci
16. OShaughnessy JA: Chemoprevention of breast cancer. JAMA
17. Kelloff GJ, Boone CW, Crowell JA, et al: Chemopreventive drug
development; Perspectives and progress. Cancer Epidemiol Biomarkers
Prev 3:85-98, 1994.
18. Lippman SM, Lee JJ, Sabichi AL: Cancer chemoprevention: Progress
and promise. J Natl Cancer Inst 90:1514-1528, 1998.
19. Buring JE, Hennekens CH: Intervention studies, in Schottenfeld D,
Fraumeni JF, Jr (eds): Cancer Epidemiology and Prevention, pp
1422-1432. New York, Oxford University Press, 1996.
20. Krinsky NI: Actions of carotenoids in biologic systems. Ann Rev
Nutr 13:561, 1993.
21. Peto R, Doll R, Buckley JD, et al: Can dietary b-carotene
materially reduce human cancer rates? Nature 290:201-209, 1981.
22. Floyd RA: Role of free radicals in carcinogenesis and brain
ischemia. FASEB J 4:2587, 1990.
23. Omenn GS: Chemoprevention of lung cancer: The rise and demise of
beta-carotene. Annu Rev Public Health 19:73-99, 1998.
24. Burton GW, Ingold KU: Beta-carotene: An unusual type of lipid
antioxidant. Science 224:569-573, 1984.
25. Palan PR, Mikhail MS, Goldberg GL, et al: Plasma levels of
b-carotene, lycopene, anthoxanthin, retinol, and a- and t-tocopherol
in cervical intraepithelial neoplasia and cervical cancer. Clin
Cancer Res 2:181-185, 1996.
26. Levy J, Bosin E, Feldman B, et al: Lycopene is a more potent
inhibitor of human cancer cell proliferation than either a-carotene
or b-carotene. Nutr Cancer 24:257-266, 1995.
27. Murakoshi M, Nishino H, Satomi Y, et al: Potent preventive action
of a-carotene against carcinogenesis: Spontaneous liver
carcinogenesis and promoting stage of lung and skin carcinogenesis in
mice are suppressed more effectively by a-carotene than by
b-carotene. Cancer Res 52:6583-6587, 1992.
28. Schrauzer GN: Selenium Mechanistic aspects of anticarcinogenic
action. Biol Trace Elem Res 33: 51-62, 1992.
29. Lippman SM, Kessler JF, Meyskens FL Jr: Retinoids as preventive
and therapeutic anticancer agents (part 1). Cancer Treat Rep 71(4):
30. Lippman SM, Kessler JF, Meyskens FL Jr: Retinoids as preventive
and therapeutic anticancer agents (part 2). Cancer Treat Rep 71(5):
31. Davies P, Lippman SM: Biologic basis of retinoid pharmacology:
Implications for cancer prevention and therapy. Adv Oncol 12:2-10, 1996.
32. Hofmann C, Eicheie C: Retinoids in development, in Spurn MB,
Roberts AB, Goodman DE (eds): The Retinoids: Biology, Chemistry, and
Medicine, 2nd ed, pp 387-442. New York, Raven Press, 1994.
33. Manglesdorf DJ, Umesono K, Evans RM: The retinoid receptors, in
Sporn MB, Roberts AB, Goodman DS (eds): The Retinoids: Biology,
Chemistry, and Medicine, 2nd ed, pp 319-349. New York, Raven Press, 1994.
34. Mangelsdorf DJ, Thummel C, Beato M, et al: The nuclear receptor
superfamily: The second decade. Cell 83:835-839, 1995.
35. Sporn MB, Roberts AB, Goodman DS (eds): The Retinoids, 2nd ed.
New York, Raven Press, 1994
36. Smith MA, Parkinson DR, Cheson BD, et al: Retinoids in cancer
therapy. J Clin Oncol 10:839-864, 1992.
37. Dabal R, Boyer CM, Berchuck A, et al: Synergistic inhibition of
ovarian cancer cell proliferation by TGF-b and retinoic acid
derivatives. Proc Annu Meet Am Assoc Cancer Res 36:A3782, 1995.
38. Hong WK, Sporn MB: Recent advances in chemoprevention of cancer.
Science 278:1073-1077, 1997.
39. Potischman N: Nutritional epidemiology of cervical neoplasia. J
Nutr 123:424-429, 1993.
40. Kvale G, Bjelke E, Cart JJ: Dietary habits and lung cancer risk.
Int J Cancer 15:397-405, 1983.
41. Hunter DJ, Stampfer MJ, Colditz GA, et al: A prospective study of
the intake of vitamins C, E, and A and the risk of breast cancer. N
Engl J Med 329:234-240, 1993.
42. Hirayama T: A large scale cohort study on cancer risk by
diet-with special reference to the risk reducing effects of
green-yellow vegetable consumption, in Hayashi Y (ed): Diet Nutrition
and Cancer, pp 41-53. Tokyo, Japan Scientific Societies Press, 1986.
43. Clinton SK, Emenhiser C, Giovannucci EL, et al: Cis-trans isomers
of lycopene in the human prostate: A role in cancer prevention? FASEB
J 9:A442, 1995.
44. Eichholzer M, Sthelin HB, Gey KF, et al: Prediction of male
cancer mortality by plasma levels of interacting vitamins: 17-year
follow-up study of the prospective Basel study. Int J Cancer 66:145-150,
45. Clark LC, Cantor KP, Allaway WH: Selenium in forage crops and
cancer mortality in US counties. Arch Environ Health 46:37-42, 1991.
46. Garland NI, Morris JS, Stampier MJ, et al: Prospective study of
toenail selenium levels and cancer among women. J Natl Cancer Inst
47. Vinceti M, Rothman KJ, Bergomi M, et al: Excess melanoma
incidence in a cohort exposed to high levels of environmental
selenium. Cancer Epidemiol Biomarkers Prev 7:853-856, 1998.
48. Hennekens CH, Buring JE, Manson JE, et al: Lack of effect of
long-term supplementation with b-carotene on the incidence of
malignant neoplasms and cardiovascular disease. N Engl J Med
49. Clark LC, Combs GF, Turnbull BW, et al: Effects of selenium
supplementation for cancer prevention in patients with carcinoma of
the skin. JAMA 276:1957-1963, 1996.
50. Taylor PR, Albanes D: Selenium, vitamin E, and prostate
cancer--ready for prime time? J Natl Cancer Inst 90:1184-1185, 1998.
51. Yoshizawa K, Willett WC, Morris SJ, et al: Study of prediagnostic
selenium level in toenails and the risk of advanced prostate cancer.
J Natl Cancer Inst 90:1219-1224, 1998.
52. Heinonen OP, Albanes D, Virtamo J, et al: Prostate cancer and
supplementation with a-tocopherol and b-carotene: Incidence and
mortality in a controlled trial. J Natl Cancer Inst 90:440-446, 1998.
53. Lotan R, Xu X-C, Lippman SM, et al: Suppression of retinoic acid
receptor b in premalignant oral lesions and its upregulation by
isotretinoin. N Engl J Med 332:1405-1410, 1995.
54. Mao L, Lee JS, Fran YH, et al: Frequent microsatellite
alterations at chromosome 9p21 and 3p14 in oral premalignant lesions
and its value in cancer risk assessment. Nature Med 2:682-685, 1996.
55. Hong WK, Lippman SM, Hittelman WN, et al: Retinoid
chemoprevention of aerodigestive cancer: From basic research to the
clinic. Clin Cancer Res 1:677-686, 1995.
56. Vokes EE, Weichselbaum RR, Lippman SM, et al: Head and neck
cancer. N Engl J Med 328:184-194, 1993.
57. Papadimitrakopoulou VA, Hong WK, Lee JS, et al: Low-dose
isotretinoin vs b-carotene to prevent oral carcinogenesis: Long-term
follow-up. J Natl Cancer Inst 89:49-50, 1997.
58. Stich HF, Rosin MP, Homby P, et al: Remission of oral
leukoplakias and micronuclei in tobacco/betel chewers treated with
b-carotene and with b-carotene plus vitamin A. Int J Cancer
59. Benner SE, Winn RJ, Lippman SM, et al: Regression of oral
leukoplakia with a-tocopherol: A community clinical oncology program
chemoprevention study. J Natl Cancer Inst 85:44-47,1993.
60. Zaridze D, Evstifeeva T, Boyle P: Chemoprevention of oral
leukoplakia and chronic esophagitis in an area of high incidence of
oral and esophageal cancer. Ann Epidemiol 3:225-234, 1993.
61. Hong WK, Endicott J, Itri LN, et al: 13-Cis-retinoic acid in the
treatment of oral leukoplakia. N Engl J Med 315:1501-1505, 1986.
62. Lippman SM, Batsakis JG, Toth BB, et al: Comparison of low-dose
isotretinoin with b-carotene to prevent oral carcinogenesis. N Engl J
Med 328:15-20, 1993.
63. Han J, Jiao L, Lu Y, et al: Evaluation of
N-4-(hydroxycarbophenyl) retinamide as a cancer prevention agent and
as a cancer chemotherapeutic agent. In Vivo 4:153-160, 1990.
64. Chiesa F, Tradati N, Marazza M, et al: 4HPR in chemoprevention of
oral leukoplakia. J Cell Biochem 17F(suppl):255-261, 1993.
65. Gouveia J, Mathe G, Hercend T, et al: Degree of bronchial
metaplasia in heavy smokers and its regression after treatment with a
retinoid. Lancet 1:710-712, 1983.
66. Arnold AM, Browman GP, Levine MN, et al: The effect of synthetic
retinoid etretinate on sputum cytology: Results from a randomized
trial. Br J Cancer 65:737-743, 1992.
67. Lee JS, Lippman SM, Benner SE, et al: A randomized
placebo-controlled trial of isotretinoin in chemoprevention of
bronchial squamous metaplasia. J Clin Oncol 12:937-945, 1994.
68. Van Poppel G, Kok FJ, Hermus RJ: b-Carotene supplementation in
smokers reduces the frequency of micronuclei in sputum. Br J Cancer
69. Van Poppel G, Poulsen H, Loft S, et al: No influence of
b-carotene on oxidative DNA damage in male smokers. J Natl Cancer
Inst 87:310-311, 1995.
70. McLarty JW, Holiday DB, Girard WM, et al: b-carotene, vitamin A,
and lung cancer chemoprevention: Results of an intermediate endpoint
study. Am J Clin Nutrition 62(suppl):1431s-1438s, 1995.
71. Pastorino U, Infante M, Maioli M, et al: Adjuvant treatment of
stage I lung cancer with high dose vitamin A. J Clin Oncol
72. Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary
tumors with isotretinoin in squamous carcinoma of the head and neck.
N Engl J Med 323:795-801, 1990.
73. Benner SE, Pajak TF, Lippman SM, et al: Prevention of second
primary tumors with 13cRA in squamous cell carcinoma of the head and
neck: Long term follow-up. J Natl Cancer Inst 86:140-141, 1994.
74. Bolla M, Lefur R, Ton Van J, et al: Prevention of second primary
tumors with etretinate in squamous cell carcinoma of the oral cavity
and oropharynx. Results of a multicenter double blind randomized
study. Eur J Cancer 30A:767-772, 1994.
75. Benner SE, Pajak TF, Lippman SM, et al: Toxicity of isotretinoin
in a chemoprevention trial to prevent second primary tumors following
head and neck. cancer. J Natl Cancer Inst 86:1799-1801, 1994.
76. Lippman SM, Hong WK: Not yet standard: Retinoids vs second
primary tumors. J Clin Oncol 11:1204-1207, 1993.
77. Lippman SM, Lee JJ, Karp DD, et al: Phase III intergroup trial of
13-cis-retinoic acid to prevent second primary tumors in stage I
non-small-cell lung cancer (NSCLC): Interim report of NCI #I91-0001
(abstract). Proc Am Soc Clin Oncol 17:456a, 1998.
78. Wu XF, Hu Y, Lippman SM: Upper aerodigestive tract cancers, in
Neugut AI, Meadows AT, Robinson E (eds): Multiple Primary Cancers:
Incidence, Etiology, Diagnosis and Prevention. Baltimore, Maryland,
Williams & Wilkins, 1998 (in press).
79. Van Zandwijk N: N-acetylcysteine and glutathione: Antioxidant and
chemopreventive properties, with special reference to lung cancer. J
Cell Biochem 22(suppl):24-32, 1995.
80. Blot WJ, Li J-Y, Taylor PR, et al: Nutrition intervention trials
in Linxian, China: Supplementation with specific vitamin/mineral
combinations, cancer incidence and disease specific mortality in the
general population. J Natl Cancer Inst 85:1483-1492, 1993.
81. Li J-Y, Taylor PR, Li B, et al: Nutrition intervention trials in
Linxian, China: Multiple vitamin/mineral supplementation cancer
incidence and disease specific among adults with esophageal
dysplasia. J Natl Cancer Inst 85:1492-1498, 1993.
82. The Alpha-Tocopherol/b-Carotene Cancer Prevention Study Group:
The effect of vitamin E and b-carotene on the incidence of lung
cancer and other cancer in male smokers. N Engl J Med 330:1029-1035, 1994.
83. Omenn GS, Goodman GE, Thornquist MD, et al: Effects of a
combination of b-carotene and vitamin A on lung cancer and
cardiovascular disease. N Engl J Med 334:1150-1155, 1996.
84. Omenn GS, Goodman GE, Thornquist MD, et al: Risk factors for lung
cancer and for intervention effects in CARET, the Beta-Carotene and
Retinol Efficacy Trial. J Natl Cancer Inst 88:1550-1559, 1996.
85. Kraemer KH, DiGiovanna JJ, Moshell AN, et al: Prevention of skin
cancer in xeroderma pigmentosum with oral isotretinoin. N Engl J Med
86. Tangrea JA, Edwards BK, Taylor PR, et al: Long-term therapy with
low dose isotretinoin for prevention of basal cell carcinoma: A
multicenter clinical trial: Isotretinoin-Basal Cell Carcinoma Study
Group. J Natl Cancer Inst 84:328-332, 1992.
87. Moon TE, Levine N, Cartmel B, et al: Effect of retinol in
preventing squamous cell skin cancer in moderate-risk subjects: A
randomized, double-blind, controlled trial. Cancer Epidemiol
Biomarkers Prev 6:949-956, 1997.
88. Levine N, Moon TE, Cartmel B, et al: Trial of retinol and
isotretinoin in skin cancer prevention: A randomized, double-blind,
controlled trial. Cancer Epidemiol Biomarkers Prev 6:957-961, 1997.
89. Greenberg ER, Baron JA, Stukel TA, et al: A clinical trial of
b-carotene to prevent basal cell and squamous cell carcinomas of the
skin. N Engl J Med 323:789-795, 1990.
90. Colditz GA: Selenium and cancer prevention: Promising results
indicate further trials required. JAMA 276:1984-1985, 1996.
91. Mitchell ME, Hittleman WN, Hong WK, et al: The natural history of
cervical intraepithelial neoplasia: An argument for intermediate
endpoint biomarkers. Cancer Epidemiol Biomarkers Prev 3: 619-626, 1994.
92. Wright TC, Kurman RJ, Ferenczy A: Precancerous lesions of the
cervix, in Kurman RJ (ed): Blausteins Pathology of the Female
Genital Tract, 4th ed,. pp 229-277. New York, Springer-Verlag, 1994.
93. De Vet HC, Knipschild PG. Willebrands D, et al: The effect of
b-carotene on the regression and progression of cervical dysplasia: A
clinical experiment. J Clinical Epidemiol 44:273-283, 1991.
94. Meyskens FL, Manetta A: Prevention of cervical intraepithelial
neoplasia and cancer. Am J Clin Nutr 62(suppl):1417s-1419s, 1995.
95. Butterworth CE, Hatch KD, Soong SJ, et al: Oral folic acid
supplementation for cervical dysplasia: A clinical intervention
trial. Am J Obstet Gynecol 166:803, 1992.
96. Childers JM, Chu J, Voight LF, et al: Chemoprevention of cervical
cancer with folic acid: A phase III Southwest Oncology Group
Intergroup study. Cancer Epidemiol Biomarkers Prev 4:155-159, 1995.
97. Romney SL, Dywer A, Slagle S, et al: Chemoprevention of cervix
cancer: Phase I-II: A feasibility study involving the topical vaginal
administration of retinyl acetate gel. Gynecol Oncol 20:109, 1985.
98. Surwit EA, Graham V, Droegmueller W, et al: Evaluation of
topically applied trans retinoic acid in the treatment of cervical
intraepithelial lesions. Am J Obstet Gynecol 143:821, 1982.
99. Meyskens FL, Graham V, Chvapil M, et al: A phase I trial of
b-all-trans-retinoic acid delivered via a collagen sponge and a
cervical cap for mild or moderate intraepithelial cervical neoplasia.
J Natl Cancer Inst 71:921, 1983
100. Weiner SA, Surwit EA, Graham VE, et al: A phase I trial of
topically applied trans retinoic acid in cervical dysplasia--clinical
efficacy. Invest New Drugs 4:241, 1986.
101. Meyskens FL, Surwit EA, Moon TE, et al: Enhancement of
regression of cervical intraepithelial neoplasia II with topically
applied all-trans retinoic acid: A randomized trial. J Natl Cancer
Inst 86:539, 1994.
102. Mitchell MF, Tortolero-Luna G, Lee JJ, et al: Phase I dose
de-escalation trial of alpha-difluoromethylornithine in patients with
grade 3 cervical intraepithelial neoplasia. Clin Cancer Res
103. Torrisi R, Parodi S, Fontana V: Effect of fenretinide on IGF-1
and IGFBP-3 in early breast cancer patients. Int J Cancer
104. Giovannucci E, Stampher MF, Colditz GA, et al: Multivitamin use,
folate, and colon cancer in women in the Nurses Health Study.
Ann Intern Med 129:517-524, 1998.
105. Greenberg ER, Baron JA, Tostenson TD, et al: A clinical trial of
antioxidant vitamins to prevent colorectal adenoma. N Engl J Med
106. MacLennan R, Macrae F, Bain C, et al: Randomized trial of intake
of fat, fiber, and b-carotene to prevent colorectal adenomas. J Natl
Cancer Inst 87:1760-1766, 1995.
107. Holmang S, Hedelin H, Anderstrom C, et al: The relationship
among multiple recurrences, progression, and prognosis of patients
with stages TA and T1 transitional cell cancer of the bladder
followed for at least 20 years. J Urol 153:1823-1827, 1995.
108. Lamm DL, Torti FM: Bladder cancer, 1996. CA Cancer J Clin
109. Kelloff GJ, Boone CW, Malone WF, et al: Development of
chemopreventive agents for bladder cancer. J Cell Biochem
110. Lamm DL, Riggs DR, Shriver JS, et al: Megadose vitamins in
bladder cancer: A double-blind clinical trial. J Urol 151:21-26, 1994.
111. Muto Y, Moriwaki H, Ninomiya M, et al: Prevention of second
primary tumors by an acyclic retinoid, polyprenoic acid, in patients
with hepatocellular carcinoma: Hepatoma Prevention Study Group. N
Engl J Med 334:1561-1567, 1996.