Practical dose delivery verification of craniospinal IMRT.

Craniospinal irradiation (CSI) using IMRT allows dose sparing to organs-at-risk (OAR) whilst conforming the dose to the target volume. Due to the complexity of treatment involving several isocenters, the dose distribution created by the inverse-planned segmented fields must be verified prior to treatment. We propose and test methods to verify dose delivery using commonly available dosimetry equipment for commissioning and routine patient-specific dose verification of craniospinal IMRT. Ten patients treated with conventional CSI were retrospectively planned with a 3-isocenter (cranial, upper spine, and lower spine) IMRT technique. The isocenters were placed 25-27 cm away from each other in the longitudinal direction but in the same lateral and anterioposterior positions. The planning target volume (PTV) was defined as the brain with a 0.5 cm margin and spinal canal with a 1.0 cm margin. The plans were prescribed to 36 Gy in 20 fractions to the PTV mean dose. Eleven beams (five cranial, three upper spine, and three lower spine) were optimized simultaneously. The dose delivered by the IMRT plans was then recalculated on several different phantoms and measured using the following methods: 1) ionization chamber inserted in a cylindrical phantom, positioned in the junction regions between cranial/upper-spine isocenters and upper-/lower-spine isocenters; 2) MapCHECK centered in the overlap regions; and 3) ArcCHECK measurement with beams from each isocenter. For 1) ± 3% dose difference and for 2) and 3) ≥ 95% of measured points with a γ-index < 1 for 3% dose difference and 3 mm distance-to-agreement were deemed clinically acceptable. The median (range) planned to measured dose differences for the ionization chamber is 0.4% (-1.5% to 3.0%) for the cranial/upper-spine field and 1.8% (-0.8% to 2.6%) for the upper-/lower-spine field overlap region. The median (range) percentage of MapCHECK diodes with a γ index < 1 for 3%/3 mm criterion is 98.0% (95.3% to 99.7%) for the cranial/upper-spine and 97.3% (95.0% to 99.6%) for the upper-/lower-spine field overlap regions. The median (range) percentage of ArcCHECK diodes with a γ index < 1 for 3%/3 mm criterion is 99.7% (97.1% to 100%). Three different methods of verifying craniospinal IMRT were compared and tested. All techniques offer different benefits and together can be used for 1) commissioning the treatment technique and, separately, for 2) patient-specific pretreatment verification measurements.

Risk-adjusted chemoradiation according to human papilloma viral status for anal cancer: a pilot study.

Background and purpose: HPV-associated or positive (HPV+) anal cancer patients may have better outcome compared to those with HPV negative (HPV-) disease. We report a planned interim analysis of a prospective registry study that tailors chemoradiation (CRT) for anal cancer according to HPV status. Materials and methods: HPV+ patients received de-escalated radiation doses of 45, 50.4 and 55.8 Gy, while HPV- received 50.4, 55.8 and 63 Gy for T1, T2 and T3/T4 disease respectively. Chemotherapy consisted of a single dose of mitomycin-C and oral capecitabine on days of RT. All patients were planned by VMAT following CT, PET/CT and MR simulation. This cohort (n = 24) had a minimum 24-month follow-up. Disease free survival (DFS) and local failure rates (LFR) were compared with 180 patients managed by standard CRT (2 cycles of mitomycin-C and 5-fluorouracil, radiation doses 50.4-63 Gy based on T-category) from 2011-2018. Propensity score comparison was performed using a retrospective to prospective 2 to 1 match based on tumor size and N-category. Results: In the HPV+ cohort (n = 20), there were 2 local failures. Two of 4 HPV- patients failed locally. The 30-month DFS and LFR were 79% and 17% respectively. Similar DFS and LFR were observed in the retrospective (80% and 15% respectively) and matched patients (76% and 16% respectively). No grade ≥3 neutropenia and febrile neutropenia were observed in the registry cohort whereas 19% and 14% respectively were seen in the retrospective patients. Conclusion: De-escalation of CRT for HPV+ anal cancer may result in decreased acute toxicities and similar cancer outcomes compared to standard CRT.

Dose-Escalated 2-Fraction Spine Stereotactic Body Radiation Therapy: 28 Gy Versus 24 Gy in 2 Daily Fractions.

PURPOSE: Stereotactic body radiation therapy (SBRT) for spine metastases improves pain response rates compared with conventional external beam radiation therapy; however, the optimal fractionation schedule is unclear. We report local control and toxicity outcomes after dose-escalated 2-fraction spine SBRT. METHODS AND MATERIALS: A prospectively maintained institutional database of over 600 patients and 1400 vertebral segments treated with spine SBRT was reviewed to identify those prescribed 28 or 24 Gy in 2 daily fractions. The primary endpoint was magnetic resonance imaging based local failure (LF), and secondary endpoints included overall survival and vertebral compression fracture (VCF). RESULTS: A total of 947 treated vertebral segments in 482 patients were identified, of which 301 segments in 159 patients received 28 Gy, and 646 segments in 323 patients received 24 Gy in 2 fractions. Median follow-up per patient was 23.5 months, and median overall survival was 49.1 months. In the 28 Gy cohort, the 6-, 12-, and 24-month cumulative incidences of LF were 3.5%, 5.4%, and 11.1%, respectively, versus 6.0%, 12.5%, and 17.6% in the 24 Gy cohort, respectively (P = .008). On multivariable analysis, 24 Gy (hazard ratio [HR], 1.525; 95% confidence interval, 1.039-2.238; P = .031), paraspinal disease extension (HR, 1.422; 95% confidence interval, 1.010-2.002; P = .044), and epidural extension in either radioresistant or radiosensitive histologies (HR, 2.117 and 1.227, respectively; P = .003) were prognostic for higher rates of LF. Risk of VCF was 5.5%, 7.6%, and 10.7% at 6, 12, and 24 months, respectively, and was similar between cohorts (P = .573). Spinal malalignment (P < .001), baseline VCF (P = .003), junctional spine location (P = .030), and greater minimum dose to 90% of planning target volume were prognostic for higher rates of VCF. CONCLUSIONS: Dose escalation to 28 Gy in 2 daily fractions was associated with improved local control without increasing the risk of VCF. The 2-year local control rates are consistent with those predicted by the Hypofractionated Treatment Effects in the Clinic spine tumor control probability model, and these data will inform a proposed dose escalation randomized trial.

Comparison of bulk electron density and voxel-based electron density treatment planning.

The use of magnetic resonance imaging (MRI) alone for radiation planning is limited by the lack of electron density for dose calculations. The purpose of this work is to evaluate the dosimetric accuracy of using bulk electron density as a substitute for computed tomography (CT)-derived electron density in intensity-modulated radiation therapy (IMRT) treatment planning of head and neck (HN) cancers. Ten clinically-approved, CT-based IMRT treatment plans of HN cancer were used for this study. Three dose distributions were calculated and compared for each treatment plan. The first calculation used CT-derived density and was assumed to be the most accurate. The second calculation used a homogeneous patient density of 1 g/cm3. For the third dose calculation, bone and air cavities were contoured and assigned a uniform density of 1.5 g/cm3 and 0 g/cm3, respectively. The remaining tissues were assigned a density of 1 g/cm3. The use of homogeneous anatomy resulted in up to 4%-5% deviations in dose distribution as compared to CT-derived electron density calculations. Assigning bulk density to bone and air cavities significantly improved the accuracy of the dose calculations. All parameters used to describe planning target volume coverage were within 2% of calculations based on CT-derived density. For organs at risk, most of the parameters were within 2%, with the few exceptions located in low-dose regions. The data presented here show that if bone and air cavities are overridden with the proper density, it is feasible to use a bulk electron density approach for accurate dose calculation in IMRT treatment planning of HN cancers. This may overcome the problem of the lack of electron density information should MRI-only simulation be performed.

Stereotactic Radiotherapy for Pancreatic Cancer: A Single-Institution Experience.

Introduction Despite treatment advances, the prognosis of locally advanced pancreatic cancer is poor. Treatment remains varied and includes systemic and radiotherapy (RT). Stereotactic body radiotherapy (SBRT), highly conformal high-dose RT per fraction, is an emerging treatment option. Materials and methods We performed a single-institution retrospective review of patients with pancreatic adenocarcinoma treated with SBRT from 2015-2017. The median dose was 27 Gy (range: 21-36 Gy) in three fractions. Endpoints included local progression (RECIST 1.1; Response Evaluation Criteria in Solid Tumors 1.1), distant metastasis, overall survival, and toxicity. Results Forty-one patients were treated, with a median follow-up of eight months. Patients who received SBRT had unresectable (49%), metastatic (17%), or borderline resectable (7%) disease, declined surgery (17%), medically inoperable (7%), or developed local recurrence following the Whipple procedure (2%). The six-month and one-year rates of local progression-free survival, distant metastasis-free survival, and overall survival were 62% and 55%, 44% and 32%, and 70% and 49%, respectively. Five patients (12%) experienced seven late gastrointestinal (GI) grade 3 events. Conclusion  SBRT may be considered a treatment option to achieve local control of pancreatic cancer and is associated with a modest risk of severe late GI toxicities. Systemic therapies remain important, given the proportion of patients who develop distant metastases.

Quantitative CT assessment of a novel direction-modulated brachytherapy tandem applicator.

PURPOSE: The purpose of this study was to quantitatively assess the CT metal-induced artifacts from a novel direction-modulated brachytherapy (DMBT) tandem applicator prototype, recently designed for cervical cancer treatments. METHODS AND MATERIALS: A water-based pelvic phantom was constructed for CT scanning. The DMBT applicator was imaged using our institutional protocol, one with higher kVp and mAs settings, and repetition of these protocols using 3-mm slices. A conventional stainless steel applicator was also scanned. In addition to the standard reconstructed images, applicator images were reconstructed using a commercial metal artifact-reduction (MAR) algorithm and an in-house-developed research algorithm. Subsequently, image quality and artifact severity were evaluated. RESULTS: Artifact severity, measured in terms of SDs in CT numbers, decreased asymptotically to background water levels with the distance away from the applicator. Artifact-reduction algorithms lead to significant and visible improvements in image quality, with >50% and >20% decrease in artifact severity achieved at a 10-mm distance for the DMBT and stainless steel applicators, respectively. Differences in artifact severity were minimal between the four imaging protocols. DMBT dimensions were the same on images with and without the commercial MAR algorithm, within <1 mm of the theoretical value. Both the commercial and in-house algorithms restored the CT numbers outside the applicator, albeit a better performance was achieved by the in-house algorithm. CONCLUSIONS: The artifacts produced by both applicators were minimized with the use of MAR algorithms. Adoption of the DMBT and stainless steel applicators for CT-guided brachytherapy is anticipated as MAR algorithms are widely available on CT scanners.

Complete blood vessel occlusion in the chick chorioallantoic membrane using two-photon excitation photodynamic therapy: implications for treatment of wet age-related macular degeneration.

Complete blood vessel occlusion is required for the treatment of age-related macular degeneration (AMD). AMD is the leading cause of blindness in developed countries and current treatment regimes have potential to cause collateral damage, or do not remove pre-existing unwanted vasculature. It has been proposed that two-photon excitation (TPE) photodynamic therapy (PDT) can be applied to cause local blood vessel occlusion without damaging surrounding retinal tissues. The in ovo chicken chorioallantoic membrane (CAM) is used as the model for vascularization in the wet form of AMD; novel techniques for the utilization of the CAM are reported. Complete occlusion of CAM vessels approximately 15 microm in diameter is achieved using the clinically approved photosensitizer Verteporfin (Visudyne, QLT, Incorporated, Vancouver, British Columbia, Canada) and TPE activation. The average and peak irradiances used for treatment are 3.3x10(6) Wcm(2) and 3.7x10(11) Wcm(2), respectively. A total fluence of 1.1x10(8) Jcm(2) is the dosage required for successful occlusion, and it is expected that for optimal conditions it will be much less. These results are the first proof-of-principle evidence in the literature that indicate TPE-PDT can be used to occlude small blood vessels. Further investigation will help determine the utility of TPE-PDT for treating wet AMD, perhaps through targeting feeder vessels.

Quantitative in vitro demonstration of two-photon photodynamic therapy using photofrin and visudyne.

Photodynamic therapy (PDT), the combined action of a photosensitizer and light to produce a cytotoxic effect, is an approved therapy for a number of diseases. At present, clinical PDT treatments involve one-photon excitation of the photosensitizer. A major limitation is that damage may be caused to healthy tissues that have absorbed the drug and lie in the beam path. Two-photon excitation may minimize this collateral damage, as the probability of absorption increases with the square of the light intensity, enabling spatial confinement of the photosensitizer activation. A potential application is the treatment of the wet-form of age-related macular degeneration, the foremost cause of central vision loss in the elderly. Herein, the commercial photosensitizers Visudyne and Photofrin are used to demonstrate quantitative in vitro two-photon PDT. A uniform layer of endothelial cells (YPEN-1) was irradiated with a Ti:sapphire laser (300 fs, 865 nm, 90 MHz) using a confocal scanning microscope. Quantification of the two-photon PDT effect was achieved using the permeability stain Hoechst 33258 and a SYTOX Orange viability stain. Visudyne was found to be around seven times more effective as a two-photon photosensitizer than Photofrin under the conditions used, consistent with its higher two-photon absorption cross-section. We also demonstrate for the first time the quadratic intensity dependence of cellular two-photon PDT. This simple in vitro method for quantifying the efficacy of photosensitizers for two-photon excited PDT will be valuable to test specifically designed two-photon photosensitizers before proceeding to in vivo studies in preclinical animal models.

The effect of prone and supine treatment positions for the pre-operative treatment of rectal cancer on organ-at-risk sparing and setup reproducibility using volumetric modulated arc therapy.

BACKGROUND AND PURPOSE: To compare organ-at-risk doses and setup reproducibility using the prone and supine orientations in volumetric modulated arc therapy (VMAT) for rectal cancer. MATERIALS AND METHODS: Seventeen consecutive rectal cancer patients undergoing preoperative radiation were selected and setup in either the prone (N = 8) or supine (N = 9) position. All patients were treated using posteriorly-applied VMAT. Bladder and small bowel dose and cone beam CT (CBCT) reproducibility metrics were retrospectively collected. RESULTS: Dose metrics for bladder and small bowel did not show significant differences between the prone and supine orientations. The prone data had a trend for smaller irradiated volumes than supine for the small bowel at lower doses-V20 (prone: 135 ± 99 cm3; supine: 201 ± 162 cm3) and V30 (prone: 78 ± 71 cm3; supine: 105 ± 106 cm3). At higher doses, the trend reversed as exemplified by the small bowel V50.4 (prone: 20 ± 28 cm3; supine: 10 ± 14 cm3). CBCT data showed that rotational errors in pitch and roll were significantly larger for the prone vs. supine orientation (pitch: 2.0° ± 1.3° vs. 0.8° ± 1.1° p < 0.001; roll: 1.0° ± 0.9° vs. 0.3° ± 0.5°, p < 0.001). CONCLUSIONS: Bladder and small bowel doses were not significantly different when comparing VMAT plans developed for the prone and supine orientations. The supine orientation demonstrated improved setup reproducibility.

Simultaneous two-photon excitation of photofrin in relation to photodynamic therapy.

Photodynamic therapy (PDT), the use of light-activated drugs (photosensitizers), is an emerging treatment modality for tumors as well as various nononcologic conditions. Single-photon (1-gamma) PDT is limited by low specificity of the photosensitizer, leading to damage to healthy tissue adjacent to the diseased target tissue. One solution is to use simultaneous two-photon (2-gamma) excitation with ultrafast pulses of near-IR light. Due to the nonlinear interaction mechanism, 2-gamma excitation with a focused beam is localized in three dimensions, allowing treatment volumes on the order of femtoliters. We propose that this will be valuable in PDT of age-related macular degeneration (AMD), which causes blindness due to abnormal choroidal neovasculature and which is currently treated by 1-gamma PDT. Here, Photofrin has been used as the photosensitizer to demonstrate proof-of-principle of 2-gamma killing of vascular endothelial cells in vitro. The 2-gamma absorption properties of Photofrin were investigated in the 750-900 nm excitation wavelength range. It was shown that 2-gamma excitation dominates over 1-gamma excitation above 800 nm. The 2-gamma absorption spectrum of Photofrin in the 800-900 nm excitation wavelength range was measured. The 2-gamma cross section decreased from about 10 GM (1 GM = 10(-50) cm4 s/photon) at 800 nm to 5 GM at 900 nm. Adherent YPEN-1 endothelial cells were then incubated with Photofrin for 24 h and then treated by PDT at 850 nm where the 1-gamma contribution was negligible. Cell death was monitored with the use of 2-gamma scanning laser microscopy. The light doses required for killing were high (6300 J cm(-2) for approximately 50% killing), but 2-gamma cytotoxicity was unequivocally demonstrated. Although Photofrin is, per se, not a good choice for 2-gamma PDT due to its low 2-gamma cross section, this work provides baseline data to guide the development of novel photosensitizers with much higher 2-gamma cross sections (>100 GM), which will be required for 2-gamma PDT of AMD (and other conditions) to be clinically practical.

4DCT Simulation With Synchronized Contrast Injection in Liver SBRT Patients.

BACKGROUND/PURPOSE: Delivering stereotactic body radiotherapy for liver metastases remains a challenge because of respiratory motion and poor visibility without intravenous contrast. The purpose of this article is to describe a novel and simple computed tomography (CT) simulation process of integrating timed intravenous contrast that could overcome the uncertainty of target delineation. METHODS AND RESULTS: The simulation involves two 4-dimensional CT (4DCT) scans. The first scan only encompasses the immediate region of the tumor and surrounding tissue, which reduces the 4DCT scan time so that it can be optimally timed with intravenous contrast injection. The second 4DCT scan covers a larger volume and is used as the primary CT data set for dose calculation, as well as patient setup verification on the treatment unit. The combination of the two 4DCT scans allows us to optimally visualize liver metastases over all phases of the breathing cycle while simultaneously acquiring a long enough 4DCT data set that is suitable for planning and patient setup verification. CONCLUSION: This simulation technique allows for a better target definition when treating liver metastases, without being invasive.

Extremely strong near-IR two-photon absorption in conjugated porphyrin dimers: quantitative description with three-essential-states model.

Two-photon absorption spectra (2PA) of a series of conjugated dimers and the corresponding monomer were studied in the near-IR region. All of the dimers show very large peak cross section values, sigma(2) = (3-10) x 10(3) GM (1 GM = 1 x 10(-50) cm(4) s photon(-1)), which is several hundred times larger than that obtained for the corresponding monomer in the same region. We explain such dramatic cooperative enhancement by a combination of several factors, such as strong enhancement of the lowest one-photon Q-transition, better resonance conditions in the three-level system, dramatic enhancement of the excited-state singlet-singlet transition, and parallel arrangement of consecutive transitions in dimers, as compared to perpendicular arrangement in the monomer. We show that the absolute values of the 2PA cross section in these molecules are quantitatively described by a quantum-mechanical expression, derived for the three-level model. We also demonstrate the possibility of singlet oxygen generation upon one- and two-photon excitation of these dimers, which makes them particularly attractive for photodynamic therapy.

Hypofractionated stereotactic radiotherapy in five daily fractions for post-operative surgical cavities in brain metastases patients with and without prior whole brain radiation.

Our purpose was to report efficacy of hypofractionated cavity stereotactic radiotherapy (HCSRT) in patients with and without prior whole brain radiotherapy (WBRT). 32 surgical cavities in 30 patients (20 patients/21 cavities had no prior WBRT and 10 patients/11 cavities had prior WBRT) were treated with image-guided linac stereotactic radiotherapy. 7 of the 10 prior WBRT patients had "resistant" local disease given prior surgery, post-operative WBRT and a re-operation, followed by salvage HCSRT. The clinical target volume was the post-surgical cavity, and a 2-mm margin applied as planning target volume. The median total dose was 30 Gy (range: 25-37.5 Gy) in 5 fractions. In the no prior and prior WBRT cohorts, the median follow-up was 9.7 months (range: 3.0-23.6) and 15.3 months (range: 2.9-39.7), the median survival was 23.6 months and 39.7 months, and the 1-year cavity local recurrence progression- free survival (LRFS) was 79 and 100%, respectively. At 18 months the LRFS dropped to 29% in the prior WBRT cohort. Grade 3 radiation necrosis occurred in 3 prior WBRT patients. We report favorable outcomes with HCSRT, and well selected patients with prior WBRT and "resistant" disease may have an extended survival favoring aggressive salvage HCSRT at a moderate risk of radiation necrosis.

Reliability of contour-based volume calculation for radiosurgery.

OBJECT: Determining accurate target volume is critical for both prescribing and evaluating stereotactic radiosurgery (SRS) treatments. The aim of this study was to determine the reliability of contour-based volume calculations made by current major SRS platforms. METHODS: Spheres ranging in diameter from 6.4 to 38.2 mm were scanned and then delineated on imaging studies. Contour data sets were subsequently exported to 6 SRS treatment-planning platforms for volume calculations and comparisons. This procedure was repeated for the case of a patient with 12 metastatic lesions distributed throughout the brain. Both the phantom and patient datasets were exported to a stand-alone workstation for an independent volume-calculation analysis using a series of 10 algorithms that included approaches such as slice stacking, surface meshing, point-cloud filling, and so forth. RESULTS: Contour data-rendered volumes exhibited large variations across the current SRS platforms investigated for both the phantom (-3.6% to 22%) and patient case (1.0%-10.2%). The majority of the clinical SRS systems and algorithms overestimated the volumes of the spheres, compared with their known physical volumes. An independent algorithm analysis found a similar trend in variability, and large variations were typically associated with small objects whose volumes were < 0.4 cm(3) and with those objects located near the end-slice of the scan limits. CONCLUSIONS: Significant variations in volume calculation were observed based on data obtained from the SRS systems that were investigated. This observation highlights the need for strict quality assurance and benchmarking efforts when commissioning SRS systems for clinical use and, moreover, when conducting multiinstitutional cross-SRS platform clinical studies.

Understanding strong two-photon absorption in pi-conjugated porphyrin dimers via double-resonance enhancement in a three-level model.

We present the two-photon absorption (2PA) spectra of a series of conjugated porphyrin dimers and show that they possess extremely large intrinsic (femtosecond) peak 2PA cross sections, up to sigma2 = 1 x 104 GM in the near-IR region; these are among the highest values measured for any organic molecule. Moreover, we demonstrate that the second-order perturbation theory applied to a simple three-level model gives a perfect quantitative description of the observed 2PA cross section. By comparing all the factors of the three-level model for dimers with those of corresponding monomer (for which sigma2 = 20 GM), we explain an approximately 500-fold cooperative enhancement in sigma2 and find that the most important factor is the strength of excited-state transition. The matrix element of dipole moment of this transition amounts gigantic values of 30-40 D for conjugated porphyrin dimers, which can be accounted for a large delocalization radius (large electron-hole separation) in this state. We also demonstrate efficient generation of singlet oxygen upon one- and two-photon excitation of these porphyrin dimers, which can be useful for two-photon initiated photodynamic therapy of cancer.