Debra H. Brinkmann

The impact of temporal inaccuracies on 4DCT image quality

Accurate delineation of target volumes is one of the critical components contributing to the success of image-guided radiotherapy treatments and several imaging modalities are employed to increase the accuracy in target identification. Four-dimensional (4D) techniques are incorporated into existing radiation imaging techniques like computed tomography (CT) to account for the mobility of the target volumes. However, these methods in some cases introduce further inaccuracies in the target delineation when further quality assurance measures are not implemented. A source of commonly observed inaccuracy is the misidentification of the respiration cycles and resulting respiration phase assignments used in the construction of the 4D patient model. The aim of this work is to emphasize the importance of optimal respiration phase assignment during the 4DCT image acquisition process and to perform a quantitative assessment of the effect of inaccurate phase assignments on the overall image quality. The accuracy of the phase assignment was assessed by comparison with an independent calculation of the respiration phases. Misplaced phase assignments manifest themselves as deformations and artifacts in reconstructed images. These effects are quantified as volumetric discrepancies in the localization of target objects represented by spherical phantoms. Measurements are performed using a fully programmable motion phantom designed and built at Mayo Clinic (Rochester, MN). Implementation of a case based independent check and correction procedure is also demonstrated with emphasis on the use of this procedure in the clinical environment. Review of clinical 4D scans performed in this institution showed discrepancies in the phase assignments in about 40% of the cases when compared to our independent calculations. It is concluded that for improved image reconstruction, an independent check of the sorting procedure should be performed for each clinical 4DCT case.

Stereotactic Body Radiation Therapy in Spinal Metastases

PURPOSE Based on reports of safety and efficacy, stereotactic body radiotherapy (SBRT) for treatment of malignant spinal tumors was initiated at our institution. We report prospective results of this population at Mayo Clinic. MATERIALS AND METHODS Between April 2008 and December 2010, 85 lesions in 66 patients were treated with SBRT for spinal metastases. Twenty-two lesions (25.8%) were treated for recurrence after prior radiotherapy (RT). The mean age of patients was 56.8 ± 13.4 years. Patients were treated to a median dose of 24 Gy (range, 10-40 Gy) in a median of three fractions (range, 1-5). Radiation was delivered with intensity-modulated radiotherapy (IMRT) and prescribed to cover 80% of the planning target volume (PTV) with organs at risk such as the spinal cord taking priority over PTV coverage. RESULTS Tumor sites included 48, 22, 12, and 3 in the thoracic, lumbar, cervical, and sacral spine, respectively. The mean actuarial survival at 12 months was 52.2%. A total of 7 patients had both local and marginal failure, 1 patient experienced marginal but not local failure, and 1 patient had local failure only. Actuarial local control at 1 year was 83.3% and 91.2% in patients with and without prior RT. The median dose delivered to patients who experienced local/marginal failure was 24 Gy (range, 18-30 Gy) in a median of three fractions (range, 1-5). No cases of Grade 4 toxicity were reported. In 1 of 2 patients experiencing Grade 3 toxicity, SBRT was given after previous radiation. CONCLUSION The results indicate SBRT to be an effective measure to achieve local control in spinal metastases. Toxicity of treatment was rare, including those previously irradiated. Our results appear comparable to previous reports analyzing spine SBRT. Further research is needed to determine optimum dose and fractionation to further improve local control and prevent toxicity.

Biopsy validation of 18F-DOPA PET and biodistribution in gliomas for neurosurgical planning and radiotherapy target delineation: results of a prospective pilot study

BACKGROUND Delineation of glioma extent for surgical or radiotherapy planning is routinely based on MRI. There is increasing awareness that contrast enhancement on T1-weighted images (T1-CE) may not reflect the entire extent of disease. The amino acid tracer (18)F-DOPA (3,4-dihydroxy-6-[18F] fluoro-l-phenylalanine) has a high tumor-to-background signal and high sensitivity for glioma imaging. This study compares (18)F-DOPA PET against conventional MRI for neurosurgical biopsy targeting, resection planning, and radiotherapy target volume delineation. METHODS Conventional MR and (18)F-DOPA PET/CT images were acquired in 10 patients with suspected malignant brain tumors. One to 3 biopsy locations per patient were chosen in regions of concordant and discordant (18)F-DOPA uptake and MR contrast enhancement. Histopathology was reviewed on 23 biopsies. (18)F-DOPA PET was quantified using standardized uptake values (SUV) and tumor-to-normal hemispheric tissue (T/N) ratios. RESULTS Pathologic review confirmed glioma in 22 of 23 biopsy specimens. Thirteen of 16 high-grade biopsy specimens were obtained from regions of elevated (18)F-DOPA uptake, while T1-CE was present in only 6 of those 16 samples. Optimal (18)F-DOPA PET thresholds corresponding to high-grade disease based on histopathology were calculated as T/N > 2.0. In every patient, (18)F-DOPA uptake regions with T/N > 2.0 extended beyond T1-CE up to a maximum of 3.5 cm. SUV was found to correlate with grade and cellularity. CONCLUSIONS (18)F-DOPA PET SUV(max) may more accurately identify regions of higher-grade/higher-density disease in patients with astrocytomas and will have utility in guiding stereotactic biopsy selection. Using SUV-based thresholds to define high-grade portions of disease may be valuable in delineating radiotherapy boost volumes.

Automated seed localization from CT datasets of the prostate

With the increasing utilization of permanent brachytherapy implants for treating carcinoma of the prostate, the importance of accurate post-treatment dose calculation also increases for assessing patient outcome and planning future treatments. An automatic method for seed localization of permanent brachytherapy implants, using CT datasets of the prostate, has been developed and tested on a phantom using an actual patient planned seed distribution. This method was also compared to results with the three-film technique for three patient datasets. The automatic method is as accurate or more accurate than the three film technique for 1 mm, 3 mm, and 5 mm contiguous CT slices, and eliminates the inter- and intra-observer variability of the manual methods. The automated method improves the localization of brachytherapy seeds while reducing the time required for the user to input information, and is demonstrated to be less operator dependent, less time consuming, and potentially more accurate than the three-film technique.

OPTIMIZATION OF INTERNAL MARGIN TO ACCOUNT FOR DOSIMETRIC EFFECTS OF RESPIRATORY MOTION

PURPOSE Use of internal margins to account for respiratory motion of the target volumes is a common strategy in radiotherapy of mobile tumors. Although efficient for tumor coverage, this expansion also risks increased toxicity to nearby healthy organs and therefore requires a careful selection of appropriate margins. In this study, we demonstrate an optimization of the internal margin used to account for respiration motion. METHODS AND MATERIALS Three-dimensional conformal treatment plans for phantom spherical target volumes as well as clinical treatment plans of 11 patients were evaluated retrospectively for optimum internal margin selection. A software-based simulation of respiration motion was performed for all cases. Moreover, the interplay with treatment setup uncertainties and corresponding margins was investigated in the phantom study. RESULTS Optimum internal margins in both phantom and patient studies were found to be substantially smaller than the actual target displacement due to respiration. The optimal internal margin was also observed to be approximately independent of the setup margins. Furthermore, no statistically significant dependence on target size and shape was observed in the group of 11 patients. CONCLUSIONS These findings present significant implications for treatment planning of mobile targets, such as tumors found in the lung and upper abdomen. We conclude that the full motion amplitude for the internal margin is overly conservative, and optimization of the internal margin provides improved sparing of nearby organs at risk without sacrificing dosimetric coverage for the target.

Decreased affinity for efflux transporters increases brain penetrance and molecular targeting of a PI3K/mTOR inhibitor in a mouse model of glioblastoma

BACKGROUND Targeting drug delivery to invasive glioma cells is a particularly difficult challenge because these cells lie behind an intact blood-brain barrier (BBB) that can be observed using multimodality imaging. BBB-associated efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) influence drug distribution to these cells and may negatively impact efficacy. To test the hypothesis that efflux transporters influence brain pharmacokinetics/pharmacodynamics of molecularly targeted agents in glioma treatment, we assessed region-specific penetrance and molecular-targeting capacity for a PI3K/mTOR kinase inhibitor that has high substrate affinity for efflux transporters (GDC-0980) and an analog (GNE-317) that was purposely designed to have reduced efflux. METHODS Brain tumor penetrance of GDC-0980 and GNE-317 was compared between FVB/n wild-type mice and Mdr1a/b(-/-)Bcrp(-/-) triple-knockout mice lacking P-gp and BCRP. C57B6/J mice bearing intracranial GL261 tumors were treated with GDC-0980, GNE-317, or vehicle to assess the targeted pharmacokinetic/pharmacodynamic effects in a glioblastoma model. RESULTS Animals treated with GNE-317 demonstrated 3-fold greater penetrance in tumor core, rim, and normal brain compared with animals dosed with GDC-0980. Increased brain penetrance correlated with decreased staining of activated p-Akt, p-S6, and p-4EBP1 effector proteins downstream of PI3K and mTOR. CONCLUSIONS GDC-0980 is subject to active efflux by P-gp and BCRP at the BBB, while brain penetrance of GNE-317 is independent of efflux, which translates into enhanced inhibition of PI3K/mTOR signaling. These data show that BBB efflux by P-gp and BCRP is therefore an important determinant in both brain penetrance and molecular targeting efficacy in the treatment of invasive glioma cells.

The addition of SPECT/CT lymphoscintigraphy to breast cancer radiation planning spares lymph nodes critical for arm drainage.

BACKGROUND This prospective cohort study was designed to determine whether the amount of radiation delivered to the nonpathological lymph nodes (LNs) that drain the arm can be significantly reduced by integrating single-photon emission computed tomography (SPECT)/computed tomography (CT) scans into radiation treatment planning. METHODS SPECT-CT scans were acquired for the 28 patients with stage I or II breast cancer and fused with the routinely obtained radiation oncology planning CT scans. Arm-draining LNs were contoured with 0.5-cm margins automatically using a threshold of 50% maximum intensity. Two treatment plans were generated: 1 per routine clinical practice (standard; STD) and the second (modified; MOD) with treatment fields modified to minimize dose to the arm-draining LNs visible on SPECT/CT images without interfering with the dosage delivered to target tissues. Participants were treated per the MOD plans. Arm volumes were measured prior to radiation and thereafter at least three subsequent 6-month intervals. RESULTS Sixty-eight level I-III arm-draining LNs were identified, 57% of which were inside the STD plan fields but could be blocked in the MOD plan fields. Sixty-five percent of arm-draining LNs in the STD versus 16% in the MOD plans received a mean of ≥10 Gy, and 26% in the STD versus 4% in the MOD plans received a mean of ≥40 Gy. Mean LN radiation exposure was 23.6 Gy (standard deviation 18.2) with the STD and 7.7 Gy (standard deviation 11.3) with the MOD plans (P<.001). No participant developed lymphedema. CONCLUSIONS The integration of SPECT/CT scans into breast cancer radiation treatment planning reduces unnecessary arm-draining LN radiation exposure and may lessen the risk of lymphedema.

Is the blood–brain barrier really disrupted in all glioblastomas? A critical assessment of existing clinical data

The blood-brain barrier (BBB) excludes the vast majority of cancer therapeutics from normal brain. However, the importance of the BBB in limiting drug delivery and efficacy is controversial in high-grade brain tumors, such as glioblastoma (GBM). The accumulation of normally brain impenetrant radiographic contrast material in essentially all GBM has popularized a belief that the BBB is uniformly disrupted in all GBM patients so that consideration of drug distribution across the BBB is not relevant in designing therapies for GBM. However, contrary to this view, overwhelming clinical evidence demonstrates that there is also a clinically significant tumor burden with an intact BBB in all GBM, and there is little doubt that drugs with poor BBB permeability do not provide therapeutically effective drug exposures to this fraction of tumor cells. This review provides an overview of the clinical literature to support a central hypothesis: that all GBM patients have tumor regions with an intact BBB, and cure for GBM will only be possible if these regions of tumor are adequately treated.

Analysis of automatic match results for cone-beam computed tomography localization of conventionally fractionated lung tumors.

PURPOSE To evaluate the dependence of an automatic match process on the size of the user-defined region of interest (ROI), the structure volume of interest (VOI), and changes in tumor volume when using cone-beam computed tomography (CBCT) for tumor localization and to compare these results with a gold standard defined by a physicians manual match. METHODS AND MATERIALS Daily CBCT images for 11 patients with lung cancer treated with conventionally fractionated radiation therapy were retrospectively matched to a reference CT image using the Varian On Board Imager software (Varian, Palo Alto, CA) and a 3-step automatic matching protocol. Matches were performed with 3 ROI sizes (small, medium, large), with and without a structure VOI (internal target volume [ITV] or planning target volume [PTV]) used in the last step. Additionally, matches were performed using an intensity range that isolated the bony anatomy of the spinal column. All automatic matches were compared with a manual match made by a physician. RESULTS The CBCT images from 109 fractions were analyzed. Automatic match results depend on ROI size and the structure VOI. Compared with the physicians manual match, automatic matches using the PTV as the structure VOI and a small ROI resulted in differences ≥ 5 mm in 1.8% of comparisons. Automatic matches using no VOI and a large ROI differed by ≥ 5 mm in 30.3% of comparisons. Differences between manual and automatic matches using the ITV as the structure VOI increased as tumor size decreased during the treatment course. CONCLUSIONS Users of automatic matching techniques should carefully consider how user-defined parameters affect tumor localization. Automatic matches using the PTV as the structure VOI and a small ROI were most consistent with a physicians manual match, and were independent of volumetric tumor changes.

Separating the dosimetric consequences of changing tumor anatomy from positional uncertainty for conventionally fractionated lung cancer patients

PURPOSE To separate the dosimetric consequences of changing tumor volume from positional uncertainty for patients undergoing conventionally fractionated lung radiation therapy (RT) and to quantify which factor has a larger impact on dose to target volumes and organs at risk (OAR). METHODS AND MATERIALS Clinical treatment plans from 20 patients who had received conventionally fractionated RT were retrospectively altered by replacing tumor and atelectasis with lung equivalent tissue in the treatment planning system calculations. To simulate positional uncertainty, the isocenter was shifted in both the altered and original plans by 2 and 5 mm in 6 directions. Rotational uncertainty was introduced by rotating each computed tomographic image set by ± 3 degrees about a superior-inferior axis extending through patient center. Additionally, after rotation the isocenter was translated back to its original point within the patient to evaluate whether purely translational corrections could minimize dosimetric consequences due to rotations. RESULTS Dosimetric statistics for each altered plan were compared with the original. Average changes in the planning target volume (PTV) receiving 95% of prescription dose (PTV V95%) resulting from changing tumor anatomy alone were approximately 0.1%. Average changes in PTV V95% resulting from positional uncertainty were greater (0.2%-4.2%) but were largely independent of whether or not the original tumor volume was present. For 3 patients, increases in volumes receiving 110% of the prescription dose were seen but were largely limited to within the PTV. Translational corrections for patient rotations were effective in minimizing differences in target coverage but had less effect on reducing the maximum spinal cord dose. CONCLUSIONS Anatomic changes alone, such as reductions in tumor volume and atelectasis, had minimal effect on the overall dose distribution. Greater dosimetric consequences were seen with positional uncertainty. With accurate patient localization, replanning during the course of treatment for conventionally fractionated lung cancer patients may not be necessary.