While being equi-toxic, the anti-tumor effect in the pre-clinical study was higher in the twice-weekly compared with the once-weekly regimen, as indicated by the significantly smaller tumors at 28 days after therapy. This difference in the therapeutic ratio in the pre-clinical study may

not have been sufficient to produce a clinically meaningful impact in patients. Another approach to improve the therapeutic index was suggested by Mason AT13387 ic50 et al. in a preclinical study of different schedules of gemcitabine concurrent with radiotherapy [25]. They determined that the best ratio of tumor response to jejunal mucosal toxicity was observed when gemcitabine was administered 24 hours before radiotherapy. This was associated with faster post-drug recovery of normal cells than tumor cells, providing a “window of opportunity”. Nevertheless, the gain in the

therapeutic ratios was small. Thus, we believe that it is unlikely that modifications in the schedule of concurrent gemcitabine-radiotherapy will substantially facilitate higher effective drug dose Anticancer Compound Library ic50 delivery. As mucosal damage has been the major toxicity observed in the current as well as all other trials of gemcitabine-RT, effective mucosal protectors may facilitate the safe delivery of higher concurrent gemcitabine doses. The radiation protector amifostine has been suggested to reduce bowel toxicity during gemcitabine-radiotherapy in patients with pancreatic cancer [26], and may have a potential to improve the therapeutic ratio in patients with HNC. However, thus far there is no compelling evidence that it can effectively reduce mucositis during chemo-RT regimens [27]. Other, new mucosal protectors require a validation of their efficacy [28] and [29]. Several features have recently emerged as markers of good prognosis in HNC, such as a history of no smoking, or remote smoking, in human papillomavirus (HPV)-related oropharyngeal cancers [30]. However, all the patients who participated in our study had advanced cAMP locoregional disease, and most of those with primary oropharyngeal cancers were heavy

smokers. Better therapies are required for these patients. Whether or not effective induction chemotherapy may improve the outcome in these poor prognosis patients is not yet clear [31] and [32]. Recent reports that hypoxic radiosensitizers and hypoxic cytotoxins are most effective in patients with P16- negative tumors (prevalent in high-risk patients), are encouraging avenues to increase local-regional tumor control, and require validation [33]. If such radiosensitizers demonstrate improvement in the therapeutic ratio, it would be feasible to administer them concurrent with RT and with systemic-acting chemotherapy such as cisplatin, which is not likely to be feasible together with gemcitabine using the schedule we described.