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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 345-347 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.0913
Head and Neck Cancer Chemoprevention Gets a Shot in the ArmEmory University, Winship Cancer Institute, Atlanta, GA Seven years ago, several ongoing and proposed clinical trials placed chemoprevention of lung and aerodigestive cancers as one of the most exciting areas for translational clinical oncologists. In 2000, Waun Ki Hong was awarded the American Society of Clinical Oncology's greatest honor based on a lifetime of accomplishments in this field. He delivered the David Karnofsky Lecture focusing on opportunities for progress in chemoprevention of cancer.1 The idea of risk stratification–based chemoprevention being translated into clinical application seemed an inevitable reality. A number of rigorously designed, translational chemoprevention trials in lung cancer were about to be launched.2 Although the phase III retinoid prevention trial in lung cancer yielded negative results,3 the randomized phase III retinoid prevention study in head and neck cancer completed accrual, with promise of the final data and their potentially transformative effect on clinical practice1 to be declared within the next few years. An adjuvant biochemoprevention approach showed that the combinations of the 13-cis-retinoic acid (13-cRA), alpha-interferon, and alpha-tocopherol appeared to be the next frontier for high-risk patients, with an article published in the Journal of Clinical Oncology showing that 80% of patients with advanced (stage III/IV) head and neck cancer were able to complete a year's treatment of this intensive regimen, and that their projected 5-year disease-free survival was 80%.4 Much has happened in the last 7 years. The field has staggered under the weight of the conclusively negative results of the phase III head and neck cancer retinoid prevention trial,5 and has seen major difficulties in accrual to the randomized bioadjuvant trial, given the disparities between the treatment arms, including the three agents and the placebo arm. Most troubling of all was that some of the most compelling data identifying chromosomal aneuploidy in upper aerodigestive track cancer lesions as the most powerful prognostic marker indicating transformation from oral leukoplakia to head and neck cancer were discredited.6 As a diverse, but dedicated, group of physicians and scientists surveyed the damage to the field done by this last unfortunate misadventure, several thought leaders began to chart the optimal path forward to bridge the gap between treatment of overt cancer and prevention of carcinogenic progression.7 To provide the proper perspective, the original data suggesting that retinoids could play a role in head and neck cancer chemoprevention harkens to the seminal work of Wolbach and Howe, who were the first to identify that cattle deprived of vitamin A were more likely to develop tumors of the upper aerodigestive tract and lung.8 Decades later, after the extensive studies on the aerodigestive tract by Slaughter,9 Auerbach,10 and others, Hong et al conducted the first randomized chemoprevention trials of retinoids in head and neck cancer.11,12 Both in oral premalignancy and second primary tumors, high-doses of retinoids seemed effective in delaying the onset of carcinogenesis across both studies. However, larger, placebo-controlled, randomized trials attempting prevention of second primary tumors with lower doses of retinoids failed to replicate these initial data.3,5 Furthermore, although combinations of multiple compounds such as 13-cRA, alpha-interferon, and alpha-tocopherol appeared to be very effective in delaying disease recurrence, patients routinely refused to enroll onto a study that randomly assigned patients to either an aggressive multidrug intervention or observation. This most promising combination, which involved intermediate doses of 13-cRA with tolerable doses of alpha-interferon and alpha-tocopherol was subsequently abandoned.4 At this point, the further development of molecular prognostic factors and risk stratification of chemoprevention trials continued to gain momentum. In a study led by Li Mao, MD, published in this issue of the Journal of Clinical Oncology, Kawaguchi et al13 identified podoplanin, a molecule whose biologic roles are incompletely understood, but which appears to be biologically important in tumorigenesis and malignant progression, in a series of patients who had enrolled onto a randomized chemoprevention study. Although the clinical trial itself showed that the active interventions attempted, namely 13-cRA versus beta-carotene and retinyl palmitate or retinyl palmitate alone, were all ineffective in preventing the development of head and neck cancer, overexpression of podoplanin was an extremely powerful predictor of progression from oral premalignant lesions to frankly invasive cancers of the head and neck.13 These data strongly supported the strategy of risk-stratified chemoprevention in lung and aerodigestive cancers, which had been advocated for more than a decade by Spitz and Hong,14 among others. However, this risk-stratified approach can move forward only if two key criteria are fulfilled. The first requires that reproducible and credible biomarkers of carcinogenic progression are identified; the second mandates that promising new agents can be brought forward into the clinic that could, by Sporn's definition, "... reverse, suppress, or prevent carcinogenic progression to frank cancer."15 Several such novel compounds are either in study or in development.
Several promising new compounds are in clinical chemoprevention trials in head and neck cancer. These include curcumin analogs, green tea extracts (GTEs), and other promising—but as yet unproven—agents such as selenium, polyphenols of pomegranate juice, Bowman-Birk inhibitor (BBI) from soybeans, and others. These represent a strategic revision from recent approaches, which were to identify what scientists and epidemiologists felt to be the most active agents in particular regimens, and try to obtain the purest compounds possible (as shown in the beta-carotene primary prevention trials16,17). In particular, green teas contain four major polyphenols: epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG).18 Multiple biologic functions have been attributed primarily to EGCG, and it seems to work as an antioxidant and inhibit cell proliferation, invasiveness, and angiogenesis mediated by signaling transduction pathways involving epidermal growth factor receptor (EGFR), nuclear factor (NF)- The National Cancer Institute has funded a series of large individual or multi-investigator grants looking at combinations of celecoxib, a selective COX-2 inhibitor with erlotinib, a small-molecule EGFR tyrosine kinase inhibitor, on the basis of extensive clinical data suggesting efficacy in head and neck cancer cell lines and xenografts.32,33 More aggressive approaches tailored to the treatment of those individuals with far advanced premalignancy could entail using targeted approaches combined with agents that show promising activity in advanced disease, such as the oncolytic adenovirus ONYX-015. We tested this agent in advanced recurrent or metastatic head and neck cancer,34 and it was brought forward as an oral mouthwash that appeared to reverse even advanced dysplasia of the oral cavity.35 To best develop these diverse and complex agents for head and neck cancer chemoprevention, and to better understand the biology of head and neck cancer, we must implement further prospective studies of molecular prognostic markers such as podoplanin and other important molecules. Only when these biomarkers are validated in prospective randomized clinical trials, and their use incorporated into molecular risk stratification models, will we have fulfilled the original promise of head and neck cancer chemoprevention. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Fadlo R. Khuri, Novartis (C) Stock Ownership: None Honoraria: Fadlo R. Khuri, Sanofi-aventis Research Funding: Fadlo R. Khuri, Genentech, Novartis, Sanofi-aventis; Dong M. Shin, Domantis Ltd, UK Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Manuscript writing: Fadlo R. Khuri, Dong M. Shin Final approval of manuscript: Fadlo R. Khuri, Dong M. Shin REFERENCES 1. Hong WK: Chemoprevention in the 21st Century: Genetics, Risk Modeling, and Molecular Targets. J Clin Oncol 18:9S–18S, 2000[Medline] 2. Hirsch F, Lippman SM: Advances in the biology of lung cancer chemoprevention. J Clin Oncol 23:3186-3197, 2005 3. Lippman SM, Lee JJ, Karp DD, et al: Randomized phase III intergroup trial of isotretinoin to prevent second primary tumors in stage-I non-small cell lung cancer. J Natl Cancer Inst 93:605-618, 2001 4. Shin DM, Khuri FR, Murphy B, et al: Combined interferon-alfa, 13-cis-retinoic acid, and alpha-tocopherol in locally advanced head and neck squamous cell carcinoma: Novel bioadjuvant phase II trial. J Clin Oncol 19:3010-3017, 2001 5. Khuri FR, Lee JJ, Lippman SM, et al: Randomized phase III trial of low-dose isotretinoin for prevention of second primary tumors in stage I and II head and neck cancer patients. J Natl Cancer Inst 98:441-450, 2006 6. Curfman GD, Morrissey S, Drazen JM: "Retraction: Sudbø J et al: DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med 344:1270-1278, 2001 and Sudbø J et al: The influence of resection and aneuploidy on mortality in oral leukoplakia. N Engl J Med 350:1405-1413, 2004." N Engl J Med 355:1927, 2006 7. Abbruzzese JL, Lippman SM: The convergence of cancer prevention and therapy in early-phase clinical drug development. Cancer Cell 6:321-326, 2004[CrossRef][Medline] 8. Wolbach SB, Howe PR: Tissue changes following deprivation of fat-soluble vitamin A. J Exp Med 42:597-630, 1925 9. Slaughter DP, Southwick HM, Smejkal W: Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6:963-968, 1953[CrossRef][Medline] 10. Auerbach O, Hammond EC, Garfinkel L: Changes in bronchial epithelium in relation to cigarette smoking, 1955-1960 vs. 1970-1977. N Engl J Med 300:381-385, 1979[Abstract] 11. Hong WK, Endicott J, Itri LM, et al: 13-cis-Retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315:1501-1505, 1986[Abstract] 12. 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 323:795-801, 1990[Abstract] 13. Kawaguchi H, El-Naggar AK, Papadimitrakopoulou V, et al: Podoplanin: A novel marker for oral cancer risk in patients with oral premalignancy. J Clin Oncol 26:354-360, 2008 14. Spitz MR, Hong WK, Amos CI, et al: A risk model for prediction of lung cancer. J Natl Cancer Inst 99:715-726, 2007 15. Sporn MB, Dunlop NM, Newton DL, et al: Prevention of chemical carcinogenesis by vitamin A and its synthetic analogues [retinoids]. Fed Proc 35:1332-1338, 1976[Medline] 16. Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group: The effect of vitamin E and beta-carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 330:1029-1035, 1994 17. Omenn GS, Goodman GE, Thornquist MD, et al: Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 334:1150-1155, 1996 18. Mukhtar H, Ahmad N: Tea polyphernols: Prevention of cancer and optimizing health. Am J Clin Nutr 71:1698A–1702S, 1703S–1704S. 19. Yang CS, Maliakal P, Meng X: Inhibition of carcinogenesis by tea. Annu Rev Pharmacol Toxicol 42:25-54, 2002[CrossRef][Medline] 20. Clinical Development Plan: Tea extracts, green tea polyphenols, epigallocatechin gallate. J Cell Biochem 26:236-257, 1996 (suppl)[CrossRef] 21. Suganuma M, Sueoka E, Sueoka N, et al: Mechanisms of cancer prevention by tea polyphenols based on inhibition of TNF-alpha expression. Biofactors 13:67-72, 2000[Medline] 22. Chow HH, Hakim IA, Vining DR, et al: Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of polyphenon E in healthy individuals. Clin Cancer Res 11:4627-4633, 2005 23. Imai K, Suga K, Nakachi K: Cancer-preventive effects of drinking green tea among a Japanese population. Prev Med 26:769-775, 1997[CrossRef][Medline] 24. Pisters KW, Newman RA, Coldman B, et al: Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol 19:1830-1838, 2001 25. Schwartz JL, Baker V, Larios E, et al: Molecular and cellular effects of green tea on oral cells of smokers: A pilot study. Mol Nutr Food Res 49:43-51, 2005[CrossRef][Medline] 26. Seeram NP, Adams LS, Henning SM, et al: In vitro anitproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem 16:360-367, 2005[CrossRef][Medline] 27. Adams LS, Seeram NP, Aggarwal BB, et al: Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells. J Agric Food Chem 54:980-985, 2006[CrossRef][Medline] 28. Pantuck AJ, Leppert JT, Zomorodian N, et al: Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res 12:4018-4026, 2006 29. Trock BJ, Hilakivi-Clark L, Clarke R: Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 98:459-471, 2006 30. Yavelow J, Collins M, Birk Y, et al: Nanomolar concentrations of Bowman-Birk soybean protease inhibitor suppress x-ray-induced transformation in vitro. Proc Natl Acad Sci U S A 82:5395-5399, 1985 31. Armstrong WB, Kennedy AR, Wan XS, et al: Clinical modulation of oral leukoplakia and protease activity by Bowman-Birk inhibitor concentrate in a phase IIa chemoprevention trial. Clin Cancer Res 6:4684-4691, 2000 32. Choe MS, Zhang X, Shin HJ, et al: Interaction between EGFR signaling and COX-2 pathways and its therapeutic implications. Mol Cancer Ther 4:1448-1455, 2005 33. Zhang X, Chen X, Choe MS, et al: Tumor growth inhibition by simultaneously blocking EGFR and cyclo-oxygenase-2 in a xenograft model. Clin Cancer Res 11:6261-6269, 2005 34. Khuri FR, Nemunaitis J, Ganly I, et al: A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 6:879-885, 2000[CrossRef][Medline] 35. Rudin CM, Cohen EEW, Vassiliki A, et al: An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol 21:4546-4552, 2003 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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B, tumor necrosis factor (TNF)-alpha, AKT, mitogen-activated protein kinase (MAPK), p53, and others.
