Incidence of High-Risk Radiologic Features in Patients Without Local Recurrence After Stereotactic Ablative Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: To investigate, in the setting of stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer, the incidence and patterns of change in high-risk radiologic features (HRFs) in patients known to have no local recurrence. METHODS AND MATERIALS: Computed tomography (CT) scans of patients treated using volumetric modulated arc therapy SABR between 2008 and 2013 were eligible if follow-up scans were available for 2 years and no local recurrences were diagnosed. All scans were reviewed at a workstation using an add-on tool for ClearCanvas (Synaptive Medical). Five clinicians who were blinded to clinical outcomes scored the presence of HRFs: enlarging opacity (EO), sequential enlarging opacity, enlarging opacity after 12 months (EO12), bulging margin, loss of linear margins, cranio-caudal growth, and loss of air bronchogram. After each review, clinicians recommended follow-up procedures based on published recommendations. RESULTS: A total of 88 patients (747 CT scans) were evaluated. The HRFs most frequently recorded by ≥3 observers on at least 1 follow-up scan were EO (64.8%), EO12 (50.0%), and sequential enlarging opacity (13.6%). Fifty-six patients developed EO within the first year after SABR, and of these, 46 also developed subsequent EO (EO12). In 76 patients who developed EO after 1 year of follow-up, 30 had not manifested EO previously. Three or more HRFs have been associated with recurrences, and this was observed on CT scan in 22.7% of patients. In their routine care, 6 patients had undergone a positron emission tomography scan because of a suspected local recurrence, and 4 underwent an attempt at biopsy. CONCLUSIONS: More than 50% of patients without a local recurrence after SABR develop HRFs. Because ≥3 HRFs were present in nearly 25% of patients, further refinement of follow-up recommendations are necessary.

Should regional ventilation function be considered during radiation treatment planning to prevent radiation-induced complications?

PURPOSE: To investigate the incorporation of pretherapy regional ventilation function in predicting radiation fibrosis (RF) in stage III nonsmall cell lung cancer (NSCLC) patients treated with concurrent thoracic chemoradiotherapy. METHODS: Thirty-seven patients with stage III NSCLC were retrospectively studied. Patients received one cycle of cisplatin-gemcitabine, followed by two to three cycles of cisplatin-etoposide concurrently with involved-field thoracic radiotherapy (46-66 Gy; 2 Gy/fraction). Pretherapy regional ventilation images of the lung were derived from 4D computed tomography via a density change-based algorithm with mass correction. In addition to the conventional dose-volume metrics (V20, V30, V40, and mean lung dose), dose-function metrics (fV20, fV30, fV40, and functional mean lung dose) were generated by combining regional ventilation and radiation dose. A new class of metrics was derived and referred to as dose-subvolume metrics (sV20, sV30, sV40, and subvolume mean lung dose); these were defined as the conventional dose-volume metrics computed on the functional lung. Area under the receiver operating characteristic curve (AUC) values and logistic regression analyses were used to evaluate these metrics in predicting hallmark characteristics of RF (lung consolidation, volume loss, and airway dilation). RESULTS: AUC values for the dose-volume metrics in predicting lung consolidation, volume loss, and airway dilation were 0.65-0.69, 0.57-0.70, and 0.69-0.76, respectively. The respective ranges for dose-function metrics were 0.63-0.66, 0.61-0.71, and 0.72-0.80 and for dose-subvolume metrics were 0.50-0.65, 0.65-0.75, and 0.73-0.85. Using an AUC value = 0.70 as cutoff value suggested that at least one of each type of metrics (dose-volume, dose-function, dose-subvolume) was predictive for volume loss and airway dilation, whereas lung consolidation cannot be accurately predicted by any of the metrics. Logistic regression analyses showed that dose-function and dose-subvolume metrics were significant (P values ≤ 0.02) in predicting volume airway dilation. Likelihood ratio test showed that when combining dose-function and/or dose-subvolume metrics with dose-volume metrics, the achieved improvements of prediction accuracy on volume loss and airway dilation were significant (P values ≤ 0.04). CONCLUSIONS: The authors' results demonstrated that the inclusion of regional ventilation function improved accuracy in predicting RF. In particular, dose-subvolume metrics provided a promising method for preventing radiation-induced pulmonary complications.

Semiautomated volumetric response evaluation as an imaging biomarker in superior sulcus tumors.

BACKGROUND: Volumetric response to therapy has been suggested as a biomarker for patient-centered outcomes. The primary aim of this pilot study was to investigate whether the volumetric response to induction chemoradiotherapy was associated with pathological complete response (pCR) or survival in patients with superior sulcus tumors managed with trimodality therapy. The secondary aim was to evaluate a semiautomated method for serial volume assessment. METHODS: In this retrospective study, treatment outcomes were obtained from a departmental database. The tumor was delineated on the computed tomography (CT) scan used for radiotherapy planning, which was typically performed during the first cycle of chemotherapy. These contours were transferred to the post-chemoradiotherapy diagnostic CT scan using deformable image registration (DIR) with/without manual editing. RESULTS: CT scans from 30 eligible patients were analyzed. Median follow-up was 51 months. Neither absolute nor relative reduction in tumor volume following chemoradiotherapy correlated with pCR or 2-year survival. The tumor volumes determined by DIR alone and DIR + manual editing correlated to a high degree (R(2) = 0.99, P < 0.01). CONCLUSION: Volumetric response to induction chemoradiotherapy was not correlated with pCR or survival in patients with superior sulcus tumors managed with trimodality therapy. DIR-based contour propagation merits further evaluation as a tool for serial volumetric assessment.

Defining target volumes for stereotactic ablative radiotherapy of early-stage lung tumours: a comparison of three-dimensional 18F-fluorodeoxyglucose positron emission tomography and four-dimensional computed tomography.

AIMS: High local control rates are achieved in stage I lung cancer using stereotactic ablative radiotherapy. Target delineation is commonly based on four-dimensional computed tomography (CT) scans. Target volumes defined by positron emission tomography/computed tomography (PET/CT) are compared with those defined by four-dimensional CT and conventional ('three-dimensional') (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT. MATERIALS AND METHODS: For 16 stage I non-small cell lung cancer tumours, six approaches for deriving PET target volumes were evaluated: manual contouring, standardised uptake value (SUV) absolute threshold of 2.5, 35% of maximum SUV (35%SUV(MAX)), 41% of SUV(MAX) (41%SUV(MAX)) and two different source to background ratio techniques (SBR-1 and SBR-2). PET-derived target volumes were compared with the internal target volume (ITV) from the modified maximum intensity projection (MIP(MOD) ITV). Volumetric and positional correlation was assessed using the Dice similarity coefficient (DSC). RESULTS: PET-based target volumes did not correspond to four-dimensional CT-based target volumes. The mean DSC relative to MIP(MOD) ITV were: PET manual = 0.64, SUV2.5 = 0.64, 35%SUV(MAX) = 0.63, 41%SUV(MAX) = 0.57. SBR-1 = 0.52, SBR-2 = 0.49. PET-based target volumes were smaller than corresponding MIP ITVs. CONCLUSIONS: Conventional three-dimensional (18)F-FDG PET-derived target volumes for lung stereotactic ablative radiotherapy did not correspond well with those derived from four-dimensional CT, including those in routine clinical use (MIP(MOD) ITV). Caution is required in using three-dimensional PET for motion encompassing target volume delineation.

Conventional 3D staging PET/CT in CT simulation for lung cancer: impact of rigid and deformable target volume alignments for radiotherapy treatment planning.

OBJECTIVE: Positron emission tomography (PET)/CT scans can improve target definition in radiotherapy for non-small cell lung cancer (NSCLC). As staging PET/CT scans are increasingly available, we evaluated different methods for co-registration of staging PET/CT data to radiotherapy simulation (RTP) scans. METHODS: 10 patients underwent staging PET/CT followed by RTP PET/CT. On both scans, gross tumour volumes (GTVs) were delineated using CT (GTV(CT)) and PET display settings. Four PET-based contours (manual delineation, two threshold methods and a source-to-background ratio method) were delineated. The CT component of the staging scan was co-registered using both rigid and deformable techniques to the CT component of RTP PET/CT. Subsequently rigid registration and deformation warps were used to transfer PET and CT contours from the staging scan to the RTP scan. Dice's similarity coefficient (DSC) was used to assess the registration accuracy of staging-based GTVs following both registration methods with the GTVs delineated on the RTP PET/CT scan. RESULTS: When the GTV(CT) delineated on the staging scan after both rigid registration and deformation was compared with the GTV(CT)on the RTP scan, a significant improvement in overlap (registration) using deformation was observed (mean DSC 0.66 for rigid registration and 0.82 for deformable registration, p = 0.008). A similar comparison for PET contours revealed no significant improvement in overlap with the use of deformable registration. CONCLUSIONS: No consistent improvements in similarity measures were observed when deformable registration was used for transferring PET-based contours from a staging PET/CT. This suggests that currently the use of rigid registration remains the most appropriate method for RTP in NSCLC.

Electronic portal image assisted reduction of systematic set-up errors in head and neck irradiation.

PURPOSE: To quantify systematic and random patient set-up errors in head and neck irradiation and to investigate the impact of an off-line correction protocol on the systematic errors. MATERIAL AND METHODS: Electronic portal images were obtained for 31 patients treated for primary supra-glottic larynx carcinoma who were immobilised using a polyvinyl chloride cast. The observed patient set-up errors were input to the shrinking action level (SAL) off-line decision protocol and appropriate set-up corrections were applied. To assess the impact of the protocol, the positioning accuracy without application of set-up corrections was reconstructed. RESULTS: The set-up errors obtained without set-up corrections (1 standard deviation (SD)=1.5-2mm for random and systematic errors) were comparable to those reported in other studies on similar fixation devices. On an average, six fractions per patient were imaged and the set-up of half the patients was changed due to the decision protocol. Most changes were detected during weekly check measurements, not during the first days of treatment. The application of the SAL protocol reduced the width of the distribution of systematic errors to 1mm (1 SD), as expected from simulations. A retrospective analysis showed that this accuracy should be attainable with only two measurements per patient using a different off-line correction protocol, which does not apply action levels. CONCLUSIONS: Off-line verification protocols can be particularly effective in head and neck patients due to the smallness of the random set-up errors. The excellent set-up reproducibility that can be achieved with such protocols enables accurate dose delivery in conformal treatments.

Multiple "slow" CT scans for incorporating lung tumor mobility in radiotherapy planning.

PURPOSE: The high local recurrence rates after radiotherapy in early-stage lung cancer may be due to geometric errors that arise when target volumes are generated using fast spiral CT scanners. A "slow" CT technique that generates more representative target volumes was evaluated. METHODS AND MATERIALS: Planning CT scans (slice thickness 3 mm, reconstruction index 2.5 mm) were performed during quiet respiration in 10 patients with peripheral lung lesions. Planning CT scans were repeated twice, followed by three slow CT scans (slice thickness 4 mm, index 3 mm, revolution time 4 s/slice). All, except the first scan, were limited to the tumor region. Three-dimensional registration of all scans was performed. The reproducibility of the imaged volumes was evaluated with each technique using (1) the common overlapping volume (COM), the component of the clinical target volume (CTV) covered by all three CT scans, and (2) the encompassing volume (SUM), which is the volume enveloped by all CTVs. RESULTS: In all patients, the target volumes generated using slow CT scans were larger than those derived using planning scans (mean ratio of planning-CTV:slow-CTV of 88.8% +/- 5.6%), and also more reproducible. The mean ratio of the respective COM:SUM volumes was 62.6% +/- 10.8% and 54.9% +/- 12.9%. CONCLUSIONS: Larger, and more reproducible, target volumes are generated for peripheral lung tumors with the use of slow CT scans, thereby indicating that slow scans can better capture tumor movement.

Dosimetric consequences of tumor mobility in radiotherapy of stage I non-small cell lung cancer--an analysis of data generated using 'slow' CT scans.

BACKGROUND: The target coverage for radiotherapy of early-stage lung cancer was evaluated using two different CT techniques. MATERIALS AND METHODS: A conventional planning CT scan and two limited scans of the tumor region were performed in seven patients with peripheral tumors. Three 'slow' scans (slice thickness 4mm, index 3mm, revolution time 4s/slice) were then performed, followed by three-dimensional image registration. Planning target volumes (PTV) were generated using these GTV-PTV margins: (a) 1cm (PTV1.0); (b) 1.5 cm (PTV1.5); and (c) 0.9, 1.0, and 0.9 cm ('PTV(clinical)') when set-up errors are avoided. RESULTS: PTVs derived from three 'slow' scans missed 1.9% of the volume derived from three planning scans for an immobile tumor and 9.3% in the case of a mobile tumor. For an immobile tumor, PTV1.5 achieved comparable coverage to that achieved using PTVclinical, which was generated from three 'slow' scans and a planning scan. For a mobile tumor, PTV(1.5) covered only 89% of the volume captured by PTVclinical. PTV1.0 resulted in inadequate target coverage in all the patients. Reductions in potential lung toxicity (V20) were achievable in six patients despite the larger GTVclinical when treatment set-up errors were minimized. CONCLUSIONS: PTVs derived using 'slow' CT scans consistently produce superior target coverage than that using conventional scans. This may account for the poor local control observed in stage I lung cancer.

Set-up verification of cervix cancer patients treated with long treatment fields; implications of a non-rigid bony anatomy.

BACKGROUND AND PURPOSE: For cervix cancer patients, treatment fields may extend up to vertebra L1. In clinical practice, set-up verification is based on measured displacements of the pelvic rim as visible in the caudal part of the treatment fields. The implications of this procedure for the positions of bony structures in the cranial part of the fields were investigated. MATERIALS AND METHODS: Twelve patients had four repeat simulator sessions. Both during treatment simulation (the reference) and the repeat sessions, anterior radiographs were acquired covering the whole treatment field. The films were used to investigate differences between the cranial and the caudal parts of the treatment field in day-to-day bony anatomy displacements. RESULTS: Both in the transversal and the longitudinal directions, these differences were significant (3.5 mm, 1 SD). Indications were found that large differences in the cranio-caudal direction may be correlated with (non-rigid) internal pelvic rim rotations around a lateral axis. In the longitudinal direction, the position of L1 correlated much better with the position of vertebra S1 than with the position of the pelvic rim, which is usually used for set-up verification. CONCLUSIONS: Due to the non-rigid bony anatomy of the studied patients, the usual set-up verification and correction procedure can result in set-up errors of 10 mm and more for structures in the cranial part of the treatment field, even in the case of a perfect set-up of the pelvic rim. Possibly, other patient set-up and immobilization procedures may result in a better day-to-day reproducibility of the 3D bony anatomy shape. (Remaining) Differences in anatomy position changes between the caudal and cranial field ends may be accounted for by using non-uniform clinical target volume-to-planning target volume margins, or by an adapted patient set-up verification and correction protocol.

Analysis and reduction of 3D systematic and random setup errors during the simulation and treatment of lung cancer patients with CT-based external beam radiotherapy dose planning.

PURPOSE: To determine the magnitude of the errors made in (a) the setup of patients with lung cancer on the simulator relative to their intended setup with respect to the planned treatment beams and (b) in the setup of these patients on the treatment unit. To investigate how the systematic component of the latter errors can be reduced with an off-line decision protocol for setup corrections. METHODS AND MATERIALS: For 39 patients with CT planning, digitally-reconstructed radiographs (DRRs) were calculated for anterior-posterior and lateral beams. Retrospectively, the position of the visible anatomy relative to the planned isocenter was compared with the corresponding position on the digitized simulator radiographs using contour match software. The setup accuracy at the treatment unit relative to the simulator setup was measured for 40 patients for at least 5 fractions per patient in 2 orthogonal beams with the aid of an electronic portal imaging device (EPID). Setup corrections were applied, based on an off-line decision protocol, with parameters derived from knowledge of the random setup errors in the studied patient group. RESULTS: The standard deviations (SD) of the simulator setup errors relative to the CT planning setup in the lateral, longitudinal, and anterior-posterior directions were 4.0, 2.8, and 2.5 mm, respectively. The SD of rotations around the anterior-posterior axis was 1.6 degrees and around the left-right axis 1.3 degrees. The setup error at the treatment unit had a small random component in all three directions (1 SD = 2 mm). The systematic components were larger, particularly in the longitudinal direction (1 SD = 3.6 mm), but were reduced with the decision protocol to 1 SD < 2 mm with, on average, 0.6 setup correction per patient. CONCLUSION: Setup errors at the simulator, which become systematic errors if the simulation defines the reference setup, were comparable to the systematic setup errors at the treatment unit in case no off-line protocol would have been applied. Hence, the omission of a separate simulation step can reduce systematic errors as efficiently as the application of an off-line correction protocol during treatment. The random errors were sufficiently small to make an off-line protocol feasible.

Beam intensity modulation using tissue compensators or dynamic multileaf collimation in three-dimensional conformal radiotherapy of primary cancers of the oropharynx and larynx, including the elective neck.

INTRODUCTION: The treatment of midline tumors in the head and neck by conventional radiotherapy almost invariably results in xerostomia. This study analyzes whether a simple three-dimensional conformal radiotherapy (3D-CRT) technique with beam intensity modulation (BIM) (using a 10-MV beam of the MM50 Racetrack Microtron) can spare parotid and submandibular glands without compromising the dose distribution in the planning target volume (PTV). METHODS: For 15 T2 tumors of the tonsillar fossa with extension into the soft palate (To) and 15 T3 tumors of the supraglottic larynx (SgL), conventional treatment plans, consisting of lateral parallel opposed beams, were used for irradiation of both the primary tumor (70 Gy) and the elective neck regions (46 Gy). Separately, for each tumor a 3-D conformal treatment plan was developed using the 3-D computer planning system, CadPlan, and Optimize, a noncommercial program to compute optimal beam profiles. Beam angles were selected with the intention of optimal sparing of the salivary glands. The intensity of the beams was then modulated to achieve a homogeneous dose distribution in the target for the given 3D-CRT techniques. The dose distributions, dose-volume histograms (DVHs) of target and salivary glands, tumor control probabilities (TCPs), salivary gland volumes absorbing a biologically equivalent dose of greater than 40 or 50 Gy, and normal tissue complication probabilities (NTCPs) of each treatment plan were computed. The parameters of the 3D-CRT plans were compared with those of the conventional plans. RESULTS: In comparison with the conventional technique, the dose homogeneity in the target volume was improved by the conformal technique for both tumor sites. In addition, for the SgL conformal technique, the average volumes of the parotid glands absorbing a BED of greater than 40 Gy (V40) decreased by 23%, and of the submandibular glands by 7% (V40) and 6% (V50). Consequently, the average NTCPs for the parotid and submandibular glands were reduced by 7% and 6%, respectively. For the To conformal techniques, the V40 of the parotid glands was decreased on average by 31%, resulting in an average reduction of the NTCP by 49%. Both the average V50 and the NTCP of the submandibular glands were decreased by 7%. CONCLUSION: For primary tumors of the oropharynx, the parotid glands could be spared to a considerable degree with the 3D-CRT technique. However, particularly the ipsilateral submandibular gland could not be spared. For primary tumors of the larynx, the 3D-CRT technique allows sparing of all salivary glands to a considerable and probably clinically relevant degree. Moreover, the conformal techniques resulted in an increased dose homogeneity in the PTV of both tumor sites.

An analysis of anatomic landmark mobility and setup deviations in radiotherapy for lung cancer.

PURPOSE: To identify thoracic structures that exhibit little internal motion during irradiation and to determine setup variations in patients with lung cancer. METHODS AND MATERIALS: Intrafractional images were generated with an electronic portal-imaging device from the AP fields of 10 patients, during several fractions. To determine the intrafractional mobility of thoracic structures, visible structures were contoured in every image and matched with a reference image by means of a cross-correlation algorithm. Setup variations were determined by comparing portal images with the digitized simulator films using the stable structures as landmarks. RESULTS: Mobility was limited in the lateral direction for the trachea, thoracic wall, paraspinal line, and aortic notch, and in the craniocaudal direction for the clavicle, aortic notch, and thoracic.wall. Analysis of patient setup revealed random deviations of 2.0 mm (1 SD) in the lateral direction and 2.8 mm in the craniocaudal direction, while the systematic deviations were 2.5 and 2.0 mm (1 SD) respectively. CONCLUSIONS: We have identified thoracic structures that exhibit little internal motion in the frontal plane, and recommend that these structures be used for verifying patient setup during radiotherapy. The daily variation in the setup of lung cancer patients at our center appears to be acceptable.

Beam intensity modulation for penumbra enhancement in the treatment of lung cancer.

PURPOSE: A treatment planning study was performed for patients with lung cancer in order to investigate the extent to which doses to critical structures could be reduced by penumbra enhancement at the superior and inferior field edges, using beam intensity modulation (BIM) with a multileaf collimator. By applying two independent published models for the prediction of the incidence of normal tissue complications, the potential for dose escalation without increasing the incidence of pneumonitis was estimated. METHODS AND MATERIALS: For 12 patients, the standard treatment technique was compared with the BIM technique using the Cadplan 3D planning system (Varian-Dosetek). Dose distributions in the healthy lung tissue were evaluated by considering both lungs minus the tumor as one functional unit. The following parameters were compared: (i) the average normalized total dose (NTD), (ii) the lung volume receiving an NTD of more than 20 Gy, and (iii) the calculated normal tissue complication probability (NTCP). RESULTS: Due to the applied BIM technique, the field lengths could be reduced by 1.4 cm for all patients, while achieving a minimum dose at the superior and inferior parts of the target of 95% of the isocenter dose. Compared to the standard technique, BIM reduced the patient mean of the average NTD for the healthy lung tissue from 16.5 to 15.3 Gy. The volume of healthy lung tissue receiving an NTD of 20 Gy or more was reduced by 9.7% (range 2.2 to 23.1%). The calculated NTCP reduced from 10.7% to 7.6% on average. The length of the esophagus that received a dose of 60 Gy or more could be reduced for 5 of the 6 stage III patients in this study. Based on equal lung NTCPs for the standard technique and the BIM technique, a mean dose escalation of 5.7 Gy (range 1.1 to 16.0 Gy) was possible for the 12 patients in this study. Based on equal average NTDs for the two techniques, the patient mean of the allowed dose escalation was 6.5 Gy (range 1.1 to 18.2 Gy). All dose escalations would be possible without exceeding the spinal cord tolerance dose. CONCLUSIONS: The BIM technique reduced the dose delivery to critical tissues. Two published methods for estimating the incidence of pneumonitis both pointed to a potential for dose escalation of 6 to 7 Gy on average with the BIM technique, without increasing the incidence of pneumonitis. For 2 of the 12 patients in this study the estimated allowed dose escalation even exceeded 15 Gy.

Simulation accuracy in radiotherapy for maxillary sinus tumors.

PURPOSE: To evaluate the accuracy and clinical importance of beam positioning during simulation of radiation treatment for tumors in the maxillary sinus. METHODS AND MATERIALS: Five patients were prepared as if they were to be treated for a maxillary sinus tumor. A three-beam computed tomography (CT) scan-based computer plan was made for each patient. The location of the central beam axis of each beam was measured, relative to bony anatomical structures. A simulation was performed using the bony references to position the radiation beams during simulation. After this, the simulation procedure was repeated by the use of a noninvasive external localization frame with a known accuracy and reproducibility within 2 mm margins. RESULTS: When defining the clinical target volume as the known tumor with a 1 cm margin, three out of five patients would suffer a partial geographical miss throughout the entire radiation treatment due to erroneous beam positioning at the simulation stage when using bony structures as a guide for beam positioning. The influence of these errors is analyzed as normal tissue complication and tumor control probabilities. CONCLUSION: When defining a planning target volume, one should consider a margin to correct for possible simulation errors. We advise the use of objective, external (and thus nonanatomical) landmarks as a reference during simulation to reduce this extra margin to a minimum. In case of simulation, using bony structures as a reference, an additional margin should be entered, depending on the simulation accuracy that can be obtained.