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Background and Purpose: To analyze the recurrence pattern in relation to target volumes and (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography in head and neck squamous cell carcinoma (HNSCC) patients treated with definitive chemoradiation., Material and Methods: 520 patients received radiotherapy for HNSCC from 2005 to 2009. Among 100 patients achieving complete clinical response and a later recurrence, 39 patients with 48 loco-regional failures had a recurrence CT scan before any salvage therapy. The estimated point of origin of each recurrence was transferred to the planning CT by deformable image co-registration. The recurrence position was then related to the delineated target volumes and iso-SUV-contours relative to the maximum standard uptake value (SUV). We defined the recurrence density as the total number of recurrences in a sub-volume divided by the sum of that volume for all patients., Results: 54% (95% CI 37-69%) of recurrences originated inside the FDG-positive volume and 96% (95% CI 86-99%) in the high dose region. Recurrence density was significantly higher in the central target volumes (P<0.0001) and increased with increasing FDG avidity (P=0.036)., Conclusions: The detailed pattern-of-failure data analysis suggests that most recurrences occur in the FDG PET positive areas or the solid tumor., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To demonstrate a data-driven dose-painting strategy based on the spatial distribution of recurrences in previously treated patients. The result is a quantitative way to define a dose prescription function, optimizing the predicted local control at constant treatment intensity. A dose planning study using the optimized dose prescription in 20 patients is performed., Methods: Patients treated at our center have five tumor subvolumes from the center of the tumor (PET positive volume) and out delineated. The spatial distribution of 48 failures in patients with complete clinical response after (chemo)radiation is used to derive a model for tumor control probability (TCP). The total TCP is fixed to the clinically observed 70% actuarial TCP at five years. Additionally, the authors match the distribution of failures between the five subvolumes to the observed distribution. The steepness of the dose-response is extracted from the literature and the authors assume 30% and 20% risk of subclinical involvement in the elective volumes. The result is a five-compartment dose response model matching the observed distribution of failures. The model is used to optimize the distribution of dose in individual patients, while keeping the treatment intensity constant and the maximum prescribed dose below 85 Gy., Results: The vast majority of failures occur centrally despite the small volumes of the central regions. Thus, optimizing the dose prescription yields higher doses to the central target volumes and lower doses to the elective volumes. The dose planning study shows that the modified prescription is clinically feasible. The optimized TCP is 89% (range: 82%-91%) as compared to the observed TCP of 70%., Conclusions: The observed distribution of locoregional failures was used to derive an objective, data-driven dose prescription function. The optimized dose is predicted to result in a substantial increase in local control without increasing the predicted risk of toxicity.

Objectives: In radiotherapy, delineation uncertainties are important as they contribute to systematic errors and can lead to geographical miss of the target. For margin computation, standard deviations (SDs) of all uncertainties must be included as SDs. The aim of this study was to quantify the interobserver delineation variation for stereotactic body radiotherapy (SBRT) of peripheral lung tumours using a cross-sectional study design., Methods: 22 consecutive patients with 26 tumours were included. Positron emission tomography/CT scans were acquired for planning of SBRT. Three oncologists and three radiologists independently delineated the gross tumour volume. The interobserver variation was calculated as a mean of multiple SDs of distances to a reference contour, and calculated for the transversal plane (SD(trans)) and craniocaudal (CC) direction (SD(cc)) separately. Concordance indexes and volume deviations were also calculated., Results: Median tumour volume was 13.0 cm(3), ranging from 0.3 to 60.4 cm(3). The mean SD(trans) was 0.15 cm (SD 0.08 cm) and the overall mean SD(cc) was 0.26 cm (SD 0.15 cm). Tumours with pleural contact had a significantly larger SD(trans) than tumours surrounded by lung tissue., Conclusions: The interobserver delineation variation was very small in this systematic cross-sectional analysis, although significantly larger in the CC direction than in the transversal plane, stressing that anisotropic margins should be applied. This study is the first to make a systematic cross-sectional analysis of delineation variation for peripheral lung tumours referred for SBRT, establishing the evidence that interobserver variation is very small for these tumours.

Purpose: Methods to estimate the likely origin of recurrences after radiation therapy for head and neck squamous cell carcinoma are compared., Methods and Materials: A total of 25 patients meeting the following inclusion criteria were randomly selected: curatively intended intensity-modulated radiotherapy planned on a positron emission tomography-computed tomography (PET/CT) scan during the period 2005-2009; squamous cell carcinoma in the oral cavity, pharynx or larynx; complete clinical response followed by locoregional recurrence; and a CT scan at recurrence before any salvage therapy. Exclusion criteria were previous cancer in the area, surgery prior to radiotherapy, or a synchronous cancer. Three methods of estimating focal points of recurrence origin and two volume overlap methods assigning the recurrences to the most central target volumes encompassing at least 50% or 95% of the recurrence volumes were tested. Treatment planning and recurrence scans were rigid and deformable co-registered in order to transfer focal points to the treatment planning scan. Double determinations of all volumes, points, and co-registrations were made., Results: The volume overlap methods assigned the recurrences to significantly more peripheral target volumes than focal methods (p < 0.0001 for all comparisons of 95% overlap vs. focal methods, p < 0.028 for all comparisons of 50% overlap vs. focal methods). Repeated registrations of the same point had higher reproducibility with deformable registration than with rigid registration (median distance 0.31 vs. 0.35 cm, p = 0.015). No significant differences were observed among the focal methods., Conclusion: Significant differences between methods were found which may affect strategies to improve radiotherapy based on pattern of failure analyses.

Background: Focal methods to determine the source of recurrence are presented, tested for reproducibility and compared to volumetric approaches with respect to the number of recurrences ascribed to the FDG-PET positive and high dose volumes., Material and Methods: Six patients treated for hypopharyngeal squamous cell carcinoma were extracted from archives. Inclusion criteria were: FDG-PET/CT for primary radiotherapy planning and clinical complete remission followed by loco-regional relapse. CT scan at the time of recurrence was also required. The recurrence volume was delineated in the follow-up scans by a radiologist. Putative points of origin (PO) of the recurrence were determined by two strategies 1) defined by an oncologist or 2) as the center-of-volume (COV) of the recurrence. The most likely recurrence point of origin on the treatment planning scan was also determined. All expert based points of origin were repeated to estimate reproducibility. The recurrence volume and PO were propagated to the treatment planning scan using a rigid transformation. Relations of the PO to target volumes, radiation doses and therapy-points-of-origin were quantified. For the volumetric methods, the overlap of the recurrence volume and target volumes was used to determine the source of the recurrence., Results: All recurrences were located in-field, but the volumetric approaches tended to designate fewer recurrences in the PET positive volume (25% for the 95% threshold, 95% confidence interval (CI):3-65%) than the observer-based methods (50% for the COV and both expert evaluations on the recurrence scan, 95% CI: 16-84%). The reproducibility of the expert POs is better on the recurrence scan than on the therapy scan., Conclusion: Volumetric approaches favor large target volumes as the source of the recurrence, thus underestimating the number of recurrences originating in the PET positive volume. Expert based and COV approaches on the recurrence scan are the most reproducible methods to determine the PO.

Background: Disease specific mortality is often used as outcome rather than total mortality in clinical trials. This approach assumes that the classification of cause of death is unbiased. We explored whether use of fungal infection-related mortality as outcome rather than total mortality leads to bias in trials of antifungal agents in cancer patients., Methods: As an estimate of bias we used relative risk of death in those patients the authors considered had not died from fungal infection. Our sample consisted of 69 trials included in four systematic reviews of prophylactic or empirical antifungal treatment in patients with cancer and neutropenia we have published previously., Results: Thirty trials met the inclusion criteria. The trials comprised 6130 patients and 869 deaths, 220 (25%) of which were ascribed to fungal infection. The relative risk of death was 0.85 (95% CI 0.75-0.96) for total mortality, 0.57 (95% CI 0.44-0.74) for fungal mortality, and 0.95 (95% CI 0.82-1.09) for mortality among those who did not die from fungal infection., Conclusion: We could not support the hypothesis that use of disease specific mortality introduces bias in antifungal trials on cancer patients as our estimate of the relative risk for mortality in those who survived the fungal infection was not increased. We conclude that it seems to be reliable to use fungal mortality as the primary outcome in trials of antifungal agents. Data on total mortality should be reported as well, however, to guard against the possible introduction of harmful treatments.