Head and Neck Cancer Chemoprevention Gets a Shot in the Arm

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. 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. Although the phase III retinoid prevention trial in lung cancer yielded negative results, 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 practice 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 alphatocopherol 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%. 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, 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. 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. 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. Decades later, after the extensive studies on the aerodigestive tract by Slaughter, Auerbach, and others, Hong et al conducted the first randomized chemoprevention trials of retinoids in head and neck cancer. 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. 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. 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 al 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. 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, 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.” 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, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 3 JANUARY 2