The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial

Second primary tumors (SPTs) develop at an annual rate of 3-7% in patients with head and neck squamous cell cancer (HNSCC). In a previous Phase III st udy, we observed that high doses of 13-cis-retinoic acid reduced the SPT ra te in this disease. In 1991, we launched an intergroup, placebo-controlled, double-blind study to evaluate the efficacy of low-dose 13-cis-retinoic ac id in the prevention of SPTs in patients with stage I or II squamous cell c arcinoma of the larynx, oral cavity, or pharynx who had been previously suc cessfully treated with surgery, radiotherapy, or both, and whose diagnoses had been established within 36 months of study entry. As of September 16, 1 999, the Retinoid Head and Neck Second Primary (HNSP) Trial had completed a ccrual with 1384 registered patients and 1191 patients randomized and eligi ble. All of the patients were followed for survival, SPT development, and i ndex cancer recurrence. Smoking status was assessed at study entry and duri ng study. Smoking cessation was confirmed biochemically by measurement of s erum cotinine levels. The annual rate of SPT development was analyzed in te rms of smoking status and tumor stage. As of May 1, 2000, SPTs have develop ed in 172 patients. Of these, 121 (70.3%) were tobacco-related SPTs, includ ing 113 in the aerodigestive tract (57 lung SPTs, 50 HNSCC SPTs, and 6 esop hageal SPTs) and 8 bladder SPTs. The remaining 51 cases included 23 prostat e adenocarcinomas, 8 gastrointestinal malignancies, 6 breast cancers, 3 mel anomas, and 11 other cancers. The annual rate of SPT development observed i n our study has been 5.1% SPT development related to smoking status was mar ginally significant (active versus never, 5.7% versus 3.5%; P = 0.053). Sig nificantly different smoking-related SPT development rates were observed in current, former, and never smokers (annual rate = 4.2%, 3.2%, and 1.9%, re spectively, overall P = 0.034; current versus never smokers, P = 0.018). St age 11 HNSCC had a higher overall annual rate of SPT development (6.4%) tha n did stage I disease (4.3%; P = 0.004). When evaluating the development of smoking-related SPTs, stage was also highly significant (4.8% for stage 11 versus 2.7% for stage I; P = 0.001). Smoking-related SPT incidence was sig nificant for site as well (larynx versus oral cavity, P 0.015; larynx versu s pharynx, P = 0.011). Primary tumors recurred at an annual rate of 2.8% in a total of 97 patients. The rate of recurrence was higher in patients with stage 11 disease (4.1% versus 2.2%, P = 0.004) as well as oral cavity site when compared with larynx (P = 0.002). This is the first large-scale prosp ective chemoprevention study evaluating smoking status and its impact on SP T development and recurrence rate in HNSCC. The results indicate significan tly higher SPT rates in active smokers versus never smokers and significant ly higher smoking-related SPT rates in active smokers versus never smokers, with intermediate rates for former smokers.