To demonstrate the large-scale clinical implementation and performance of an automated treatment planning methodology for tangential breast intensity modulated radiation therapy (IMRT).
Automated ...planning was used to prospectively plan tangential breast IMRT treatment for 1661 patients between June 2009 and November 2012. The automated planning method emulates the manual steps performed by the user during treatment planning, including anatomical segmentation, beam placement, optimization, dose calculation, and plan documentation. The user specifies clinical requirements of the plan to be generated through a user interface embedded in the planning system. The automated method uses heuristic algorithms to define and simplify the technical aspects of the treatment planning process.
Automated planning was used in 1661 of 1708 patients receiving tangential breast IMRT during the time interval studied. Therefore, automated planning was applicable in greater than 97% of cases. The time for treatment planning using the automated process is routinely 5 to 6 minutes on standard commercially available planning hardware. We have shown a consistent reduction in plan rejections from plan reviews through the standard quality control process or weekly quality review multidisciplinary breast rounds as we have automated the planning process for tangential breast IMRT. Clinical plan acceptance increased from 97.3% using our previous semiautomated inverse method to 98.9% using the fully automated method.
Automation has become the routine standard method for treatment planning of tangential breast IMRT at our institution and is clinically feasible on a large scale. The method has wide clinical applicability and can add tremendous efficiency, standardization, and quality to the current treatment planning process. The use of automated methods can allow centers to more rapidly adopt IMRT and enhance access to the documented improvements in care for breast cancer patients, using technologies that are widely available and already in clinical use.
Purpose:
To evaluate the utility of a new complexity metric, the modulation complexity score (MCS), in the treatment planning and quality assurance processes and to evaluate the relationship of the ...metric with deliverability.
Methods:
A multisite (breast, rectum, prostate, prostate bed, lung, and head and neck) and site-specific (lung) dosimetric evaluation has been completed. The MCS was calculated for each beam and the overall treatment plan. A 2D diode array (MapCHECK™, Sun Nuclear, Melbourne, FL) was used to acquire measurements for each beam. The measured and planned dose (PINNACLE
3, Phillips, Madison, WI) was evaluated using different percent differences and distance to agreement (DTA) criteria (3%/3 mm and 2%/1 mm) and the relationship between the dosimetric results and complexity (as measured by the MCS or simple beam parameters) assessed.
Results:
For the multisite analysis (243 plans total), the mean MCS scores for each treatment site were breast (0.92), rectum (0.858), prostate (0.837), prostate bed (0.652), lung (0.631), and head and neck (0.356). The MCS allowed for compilation of treatment site-specific statistics, which is useful for comparing different techniques, as well as for comparison of individual treatment plans with the typical complexity levels. For the six plans selected for dosimetry, the average diode percent pass rate was 98.7% (minimum of 96%) for 3%/3 mm evaluation criteria. The average difference in absolute dose measurement between the planned and measured dose was 1.7 cGy. The detailed lung analysis also showed excellent agreement between the measured and planned dose, as all beams had a diode percentage pass rate for 3%/3 mm criteria of greater than 95.9%, with an average pass rate of 99.0%. The average absolute maximum dose difference for the lung plans was 0.7 cGy. There was no direct correlation between the MCS and simple beam parameters which could be used as a surrogate for complexity level (i.e., number of segments or MU). An evaluation criterion of 2%/1 mm reliably allowed for the identification of beams that are dosimetrically robust. In this study we defined a robust beam or plan as one that maintained a diode percentage pass rate greater than 90% at 2%/1 mm, indicating delivery that was deemed accurate when compared to the planned dose, even under stricter evaluation criterion. MCS and MU threshold criteria were determined by defining a required specificity of 1.0. A MCS threshold of 0.8 allowed for identification of robust deliverability with a sensitivity of 0.36. In contrast, MU had a lower sensitivity of 0.23 for a threshold of 50 MU.
Conclusions:
The MCS allows for a quantitative assessment of plan complexity, on a fixed scale, that can be applied to all treatment sites and can provide more information related to dose delivery than simple beam parameters. This could prove useful throughout the entire treatment planning and QA process.
Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), ...candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1).
Endpoints based on RECISTv1.1 objective response rate (ORR)/progression-free survival (PFS) or irRECIST immune-related ORR (irORR)/immune-related PFS (irPFS) were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing.
Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 ≥1% had longer median irPFS and higher irORR. High percentage of CD8
tumor-infiltrating cells (TIC) that are PD-1
TIM-3
LAG-3
(% CD8
PD-1
TIM-3
LAG-3
TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8
PD-1
TIM-3
LAG-3
TIC identified three groups of patients for which irPFS and irORR were significantly different.
Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8
TIC may predict outcome on nivolumab in mccRCC.
To investigate the effect of breathing motion and dose accumulation on the planned radiotherapy dose to liver tumors and normal tissues using deformable image registration.
Twenty-one free-breathing ...stereotactic liver cancer radiotherapy patients, planned on static exhale computed tomography (CT) for 27-60 Gy in six fractions, were included. A biomechanical model-based deformable image registration algorithm retrospectively deformed each exhale CT to inhale CT. This deformation map was combined with exhale and inhale dose grids from the treatment planning system to accumulate dose over the breathing cycle. Accumulation was also investigated using a simple rigid liver-to-liver registration. Changes to tumor and normal tissue dose were quantified.
Relative to static plans, mean dose change (range) after deformable dose accumulation (as % of prescription dose) was -1 (-14 to 8) to minimum tumor, -4 (-15 to 0) to maximum bowel, -4 (-25 to 1) to maximum duodenum, 2 (-1 to 9) to maximum esophagus, -2 (-13 to 4) to maximum stomach, 0 (-3 to 4) to mean liver, and -1 (-5 to 1) and -2 (-7 to 1) to mean left and right kidneys. Compared to deformable registration, rigid modeling had changes up to 8% to minimum tumor and 7% to maximum normal tissues.
Deformable registration and dose accumulation revealed potentially significant dose changes to either a tumor or normal tissue in the majority of cases as a result of breathing motion. These changes may not be accurately accounted for with rigid motion.
Cone-beam computed tomography (CBCT) in-room imaging allows accurate inter- and intrafraction target localization in stereotactic body radiotherapy of lung tumors.
Image-guided stereotactic body ...radiotherapy was performed in 28 patients (89 fractions) with medically inoperable Stage T1-T2 non-small-cell lung carcinoma. The targets from the CBCT and planning data set (helical or four-dimensional CT) were matched on-line to determine the couch shift required for target localization. Matching based on the bony anatomy was also performed retrospectively. Verification of target localization was done using either megavoltage portal imaging or CBCT imaging; repeat CBCT imaging was used to assess the intrafraction tumor position.
The mean three-dimensional tumor motion for patients with upper lesions (n = 21) and mid-lobe or lower lobe lesions (n = 7) was 4.2 and 6.7 mm, respectively. The mean difference between the target and bony anatomy matching using CBCT was 6.8 mm (SD, 4.9, maximum, 30.3); the difference exceeded 13.9 mm in 10% of the treatment fractions. The mean residual error after target localization using CBCT imaging was 1.9 mm (SD, 1.1, maximum, 4.4). The mean intrafraction tumor deviation was significantly greater (5.3 mm vs. 2.2 mm) when the interval between localization and repeat CBCT imaging (n = 8) exceeded 34 min.
In-room volumetric imaging, such as CBCT, is essential for target localization accuracy in lung stereotactic body radiotherapy. Imaging that relies on bony anatomy as a surrogate of the target may provide erroneous results in both localization and verification.
To present an automated technique for two-field tangential breast intensity-modulated radiotherapy (IMRT) treatment planning.
A total of 158 planned patients with Stage 0, I, and II breast cancer ...treated using whole-breast IMRT were retrospectively replanned using automated treatment planning tools. The tools developed are integrated into the existing clinical treatment planning system (Pinnacle(3)) and are designed to perform the manual volume delineation, beam placement, and IMRT treatment planning steps carried out by the treatment planning radiation therapist. The automated algorithm, using only the radio-opaque markers placed at CT simulation as inputs, optimizes the tangential beam parameters to geometrically minimize the amount of lung and heart treated while covering the whole-breast volume. The IMRT parameters are optimized according to the automatically delineated whole-breast volume.
The mean time to generate a complete treatment plan was 6 min, 50 s ± 1 min 12 s. For the automated plans, 157 of 158 plans (99%) were deemed clinically acceptable, and 138 of 158 plans (87%) were deemed clinically improved or equal to the corresponding clinical plan when reviewed in a randomized, double-blinded study by one experienced breast radiation oncologist. In addition, overall the automated plans were dosimetrically equivalent to the clinical plans when scored for target coverage and lung and heart doses.
We have developed robust and efficient automated tools for fully inversed planned tangential breast IMRT planning that can be readily integrated into clinical practice. The tools produce clinically acceptable plans using only the common anatomic landmarks from the CT simulation process as an input. We anticipate the tools will improve patient access to high-quality IMRT treatment by simplifying the planning process and will reduce the effort and cost of incorporating more advanced planning into clinical practice.
Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent ...adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8
T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.
Suppression of T-cell responses by host-derived regulatory factors is a key event leading to viral persistence. Antibody blockade of either IL-10 or programmed death-ligand 1 (PD-L1) during viral ...persistence enhances T-cell function and reduces viral titers. Because blockade of these immunoregulatory networks represents a powerful approach to establish immune control during persistent infection, it is important to determine whether these immunoinhibitory factors act independently or jointly and if combined blockade of these factors further enhances T-cell immunity and viral clearance. Herein, we demonstrate that the IL-10 and PD-L1 immunosuppressive pathways are mechanistically distinct. As a result, simultaneous blockade of IL-10 and PD-L1 was significantly more effective in restoring antiviral T-cell responses than blockade of either alone, and led to substantially enhanced control of an established persistent viral infection. Thus, combinatorial blockade of multiple immune-regulatory molecules may ultimately restore the T-cell responses required to tip the balance from viral persistence to immune-mediated control or elimination of persistent infection.
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