On Monday, November 1, the ASTRO membership heard a Keynote Address by Dr. Waun Ki Hong,[1] Professor of Medicine and Chair of the Department of Head and Neck and Thoracic Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston. Dr. Hong is a world-renowned expert in the use of retinoids as chemoprevention for development of malignancies in the aerodigestive tract. Dr. Hong studied successfully treated head and neck cancer patients given retinoic acid as an adjuvant to prevent second primary tumors from occurring. In this placebo-controlled trial, 1 year of retinoic acid treatment provided a striking decrease in the development of second primary tumors. On long-term follow-up, however, the absolute numbers of tumors which developed up to 3 years were significantly reduced in the treatment group, after which time the rate of developing second tumors in the retinoic acid group was the same as in the placebo group. Thus, the effect of retinoic acid as a chemopreventative adjuvant was lost after the 3-year point. The molecular basis for these clinical observations was then reviewed by Dr. Hong. It is known that retinoic acid is important in the control of cellular proliferation in the epithelium. There have been six retinoic acid receptor subtypes identified. Of these receptor subtypes, the beta-retinoic acid receptor (RAR-beta) appears to be the key marker for some of the activities of retinoic acid in these patients. In normal tissues, all six receptor subtypes are expressed. However, in patients with leukoplakia, the beta subtype is essentially not expressed in those lesions. After 3 months of retinoic acid therapy, however, there is upregulation of RAR-beta, which corresponded to regression of the lesion. This suggests that RAR-beta can be used as a biomarker for successful therapy with retinoic acid as a chemopreventative. In terms of resistance to retinoids, Dr. Hong defined three groups. After retinoic acid therapy, approximately 60% of patients with lesions of leukoplakia show complete reversal of these lesions. Forty percent, however, are de novo resistant to the retinoic acid derivative, and, of the 60% who originally respond, approximately 50% go on to become resistant to retinoic acid effects and redevelop leukoplakia and can develop aerodigestive cancer. In order to overcome primary resistance, Dr. Hong's group developed a combination approach using retinoic acid, interferon, and vitamin E as a combined chemopreventative regimen. The reasoning behind this combination came from the preclinical laboratory, where it was noted that vitamin E actually decreased retinoic acid side effects and was chemopreventative in and of itself, and interferon was synergistic in reversing premalignant lesions when used with retinoic acid. In the 31 patients evaluable on this trial, there was a disparity in response based on the site of leukoplakia. In patients whose larynx tissue was primarily affected, 50% of those patients showed good resolution of the premalignant lesions. However, in the patients with oral lesions, only 1 patient showed reversal of the premalignant lesion. The reason underlying this disparity is not understood. Further work on dysplastic lesions in relation to response to retinoids as chemopreventatives has shown that p53 mutations are an important factor determining response. In those patients with dysplastic lesions with normal p53 protein present, a high chance for response to retinoic acid derivatives was found. However, in patients with mutated p53, their rate of response to retinoic acid effects was poor. To further analyze results of these trials, Dr. Hong's group developed the capability of evaluating loss of heterozygosity (LOH) for certain key genes containing tumor-suppressor functions. The most notable of these is probably in the 9p area. It was found that even in mucosa which showed complete phenotypic reversion to apparently normal, LOH for the 9p region was often observed. Dr. Hong called this phenomenon "molecular scarring." He went on to say that he felt that it was the persistence of these genetic "scars" that leads to the eventual reemergence of dysplastic and frankly malignant tissue after chemoprevention is stopped. Obviously, since only a few sites in the genome were assayed for LOH, it is likely that other sites of genetic abnormalities also persist in these patients. Dr. Hong's talk was divided into three parts. The first described data concerning what molecular and genetic events were necessary for induction of the primary cancer, and then which of those events were the same or different in induction of a secondary tumor. The second part described the use of retinoids as chemopreventative agents, and the third described mechanisms underlying resistance to chemoprevention using retinoids, as well as strategies for overcoming these mechanisms of resistance. Ann's NOTE: This is yet another example of Vitamin A being used to fight/reverse malignancy. It is significant that this researcher used combination vitamin therapy for a better response. I would like to see a trial of all the antioxidants used in combination and have suggested this to FDA (Food and Drug Administration) and to NCCAM (National Center for Complementary and Alternative Medicine). Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.