Associations Between Radiation Doses To Pharyngeal Regions And Severe Late Toxicity In Head And Neck Cancer Patients Treated With Concurrent Chemoradiotherapy - An Rtog Analysis

Concurrent chemoradiotherapy (CCRT) for Stage III/IV head and neck cancer improves survival over RT alone, but is associated with increased toxicity, including late pharyngolaryngeal complications. This analysis was done to determine if doses (by 2-D dosimetric analyses) to regions of the pharynx are associated severe late toxicity. This is a retrospective review of pts treated with CCRT regimens from three RTOG trials: 1. RTOG 91-11 Arm 2 (XRT/high-dose cisplatin); 2. RTOG 97-03 Arms 1 and 3 (XRT + 5-FU/cisplatin or cisplatin/paclitaxel); and 3. RTOG 99-14 (accelerated XRT/high dose cisplatin). These studies did not use 3-D conformal RT or IMRT. Dosimetric data including simulation and portal films, treatment prescriptions/records and 2-D dosimetry records were evaluated for 154 evaluable pts (pts NED for at least 2 years and for whom all technical data were available). Reviewers were blinded to pt toxicity outcomes during these analyses. Cumulative doses to four pharyngeal regions were determined for each pt.: 1. Superior oropharynx (adjacent to soft palate); 2. Inferior oropharynx (adjacent to epiglottic tip); 3. Mid-hypopharynx (adjacent to arytenoid cartilage); and 4. Inferior hypopharynx (pharyngoesophageal inlet). Severe late toxicity was defined as Grade 3+ pharyngolaryngeal dysfunction and/or requirement for a long-term feeding tube. Multivariate analysis was performed to determine factors predictive of severe late toxicity. Severe late toxicity was present in 71 of 154 evaluable pts (46%). The rates of severe late toxicity were similar for the three RTOG studies. Pts with severe late toxicity were more likely to be older (mean age 59.7 vs. 54.6; p = 0.0009) and more likely to have KPS <90% (23% vs. 11%; p = 0.05). All other pre-treatment characteristics, XRT tumor dose, and chemo delivery were similar between patients with and without severe late toxicity. Dosimetric analysis showed no significant differences in radiation doses to the superior or inferior oropharynx (p = 0.87 and p = 0.77 respectively). However, radiation doses to the superior and inferior hypopharynx were significantly higher in the group with severe late toxicity (p = 0.015 and p = 0.025, respectively). On multivariate analysis, the only statistically significant covariates associated with severe late toxicity were age (odds ratio 1.062; p = 0.002) and dose to the inferior hypopharynx (odds ratio 1.023; p = 0.016) (both analyzed as continuous variables). The median inferior hypopharynx dose among pts with severe late toxicity (cases) was 58 Gy, compared with 50.6 Gy among pts without severe late toxicity (controls). Higher dose to the inferior hypopharynx is associated with a greater risk of severe late toxicity among pts treated with CCRT for head and neck cancer. More detailed and rigorous dose-volume analyses based on 3-D/IMRT datasets are required, both to confirm this finding and to elucidate future means of decreasing late radiation complications.