K. Kian Ang

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. RESULTS: The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)

PURPOSE: Concurrent chemoradiotherapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases both local tumor control and toxicity. This study evaluates clinical factors that are associated with and might predict severe late toxicity after CCRT. METHODS: Patients were analyzed from a subset of three previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3 to 4 pharyngeal/laryngeal toxicity (RTOG/European Organisation for the Research and Treatment of Cancer late toxicity scoring system) and/or requirement for a feeding tube >or= 2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Case-control analysis was performed, with a multivariable logistic regression model that included pretreatment and treatment potential factors. RESULTS: A total of 230 patients were assessable for this analysis: 99 patients with severe late toxicities and 131 controls; thus, 43% of assessable patients had a severe late toxicity. On multivariable analysis, significant variables correlated with the development of severe late toxicity were older age (odds ratio 1.05 per year; P = .001); advanced T stage (odds ratio, 3.07; P = .0036); larynx/hypopharynx primary site (odds ratio, 4.17; P = .0041); and neck dissection after CRT (odds ratio, 2.39; P = .018). CONCLUSION: Severe late toxicity after CCRT is common. Older age, advanced T-stage, and larynx/hypopharynx primary site were strong independent risk factors. Neck dissection after CCRT was associated with an increased risk of these complications.

A greyscale-based fully automatic deformable image registration algorithm, originally known as the 'demons' algorithm, was implemented for CT image-guided radiotherapy. We accelerated the algorithm by introducing an 'active force' along with an adaptive force strength adjustment during the iterative process. These improvements led to a 40% speed improvement over the original algorithm and a high tolerance of large organ deformations. We used three methods to evaluate the accuracy of the algorithm. First, we created a set of mathematical transformations for a series of patient's CT images. This provides a 'ground truth' solution for quantitatively validating the deformable image registration algorithm. Second, we used a physically deformable pelvic phantom, which can measure deformed objects under different conditions. The results of these two tests allowed us to quantify the accuracy of the deformable registration. Validation results showed that more than 96% of the voxels were within 2 mm of their intended shifts for a prostate and a head-and-neck patient case. The mean errors and standard deviations were 0.5 mm ± 1.5 mm and 0.2 mm ± 0.6 mm, respectively. Using the deformable pelvis phantom, the result showed a tracking accuracy of better than 1.5 mm for 23 seeds implanted in a phantom prostate that was deformed by inflation of a rectal balloon. Third, physician-drawn contours outlining the tumour volumes and certain anatomical structures in the original CT images were deformed along with the CT images acquired during subsequent treatments or during a different respiratory phase for a lung cancer case. Visual inspection of the positions and shapes of these deformed contours agreed well with human judgment. Together, these results suggest that the accelerated demons algorithm has significant potential for delineating and tracking doses in targets and critical structures during CT-guided radiotherapy.

There is strong clinical and radiobiological evidence that protraction of overall treatment time has an adverse influence on the radiocurability of certain human tumors. Overall treatment time can be reduced without recourse to large dose fractions by the use of accelerated fractionation, but in patients with head and neck cancer acute mucosal reactions limit the extent to which treatment can be accelerated. Three different prototypical schedules for accelerated fractionation have been devised to avoid exceeding acute mucosal tolerance. Type A consists of an intensive short course in which the overall duration of treatment is markedly decreased with a corresponding substantial reduction of total dose; type B achieves a modest decrease in overall time without reduction of total dose by using a split-course technique; type C also achieves a modest decrease in overall time without reduction of total dose by means of the concomitant boost technique. A hybrid schedule combining features of types B and C allows additional shortening of overall treatment time without reduction of total dose. Available radiobiological and clinical data suggest that schedules of types B or C which do not compromise total dose are generally preferable to those of type A in which there is a trade-off between total dose and overall time. For a given total dose and overall time, a continuous treatment of type C is likely to produce more cell kill than a split-course of type B, although the latter will be better tolerated. Because of the increased acute toxicity associated with all schedules of accelerated fractionation, rational selection of patients for such treatment is important. New techniques to measure the potential doubling time of human tumors in vivo offer this prospect.