Comparative study of SRS end-to-end QA processes of a diode array device and an anthropomorphic phantom loaded with GafChromic XD film.

PURPOSE: End-to-end testing (E2E) is a necessary process for assessing the readiness of the stereotactic radiosurgery (SRS) program and annual QA of an SRS system according to the AAPM MPPG 9a. This study investigates the differences between using a new SRS MapCHECK (SRSMC) system and an anthropomorphic phantom film-based system in a large network with different SRS delivery techniques. METHODS AND MATERIALS: Three SRS capable Linacs (Varian Medical Systems, Palo Alto, CA) at three different regional sites were chosen to represent a hospital network, a Trilogy with an M120 multi-leaf collimator (MLC), a TrueBeam with an M120 MLC, and a TrueBeam Stx with an HD120 MLC. An anthropomorphic STEEV phantom (CIRS, Norfolk, VA) and a phantom/diode array: StereoPHAN/SRSMC (Sun Nuclear, Melbourne, FL) were CT scanned at each site. The new STV-PHANTOM EBT-XD films (Ashland, Bridgewater, NJ) were used. Six plans with various complexities were measured with both films and SRSMC in the StereoPHAN to establish their dosimetric correlations. Three SRS cranial plans with a total of sixteen fields using dynamic conformal arc and volumetric-modulated arc therapy, with 1-4 targets, were planned with Eclipse v15.5 treatment planning system (TPS) using a custom SRS beam model for each machine. The dosimetric and localization accuracy were compared. The time of analysis for the two systems by three teams of physicists was also compared to assess the throughput efficiency. RESULTS: The correlations between films and SRSMC were found to be 0.84 (p = 0.03) and 0.16 (p = 0.76) for γ (3%, 1 mm) and γ (3%, 2 mm), respectively. With film, the local dose differences (ΔD) relative to the average dose within the 50% isodose line from the three sites were found to be -3.2%-3.7%. The maximum localization errors (Elocal ) were found to be within 0.5 ± 0.2 mm. With SRSMC, the ΔD was found to be within 5% of the TPS calculation. Elocal were found to be within 0.7 to 1.1 ± 0.4 mm for TrueBeam and Trilogy, respectively. Comparing with film, an additional uncertainty of 0.7 mm was found with SRSMC. The delivery and analysis times were found to be 6 and 2 h for film and SRSMC, respectively. CONCLUSIONS: The SRS MapCHECK agrees dosimetrically with the films within measurement uncertainties. However, film dosimetry shows superior sub-millimeter localization resolving power for the MPPG 9a implementation.

Durable 5-year local control for resected brain metastases with early adjuvant SRS: the effect of timing on intended-field control.

BACKGROUND: Adjuvant stereotactic radiosurgery (SRS) improves the local control of resected brain metastases (BrM). However, the dependency of long-term outcomes on SRS timing relative to surgery remains unclear. METHODS: Retrospective analysis of patients treated with metastasectomy-plus-adjuvant SRS at Memorial Sloan Kettering Cancer Center (MSK) between 2013 and 2016 was conducted. Kaplan-Meier methodology was used to describe overall survival (OS) and cumulative incidence rates were estimated by type of recurrence, accounting for death as a competing event. Recursive partitioning analysis (RPA) and competing risks regression modeling assessed prognostic variables and associated events of interest. RESULTS: Two hundred and eighty-two patients with BrM had a median OS of 1.5 years (95% CI: 1.2-2.1) from adjuvant SRS with median follow-up of 49.8 months for survivors. Local surgical recurrence, other simultaneously SRS-irradiated site recurrence, and distant central nervous system (CNS) progression rates were 14.3% (95% CI: 10.1-18.5), 4.9% (95% CI: 2.3-7.5), and 47.5% (95% CI: 41.4-53.6) at 5 years, respectively. Median time-to-adjuvant SRS (TT-SRS) was 34 days (IQR: 27-39). TT-SRS was significantly associated with surgical site recurrence rate (P = 0.0008). SRS delivered within 1 month resulted in surgical site recurrence rate of 6.1% (95% CI: 1.3-10.9) at 1-year, compared to 9.2% (95% CI: 4.9-13.6) if delivered between 1 and 2 months, or 27.3% (95% CI: 0.0-55.5) if delivered >2 months after surgery. OS was significantly lower for patients with TT-SRS >~2 months. Postoperative length of stay, discharge to a rehabilitation facility, urgent care visits, and/or disease recurrence between surgery and adjuvant SRS associated with increased TT-SRS. CONCLUSIONS: Adjuvant SRS provides durable local control. However, delays in initiation of postoperative SRS can decrease its efficacy.

Accuracy of surface-guided patient setup for conventional radiotherapy of brain and nasopharynx cancer.

PURPOSE: To evaluate the accuracy of surface-guided radiotherapy (SGRT) in cranial patient setup by direct comparison between optical surface imaging (OSI) and cone-beam computed tomography (CBCT), before applying SGRT-only setup for conventional radiotherapy of brain and nasopharynx cancer. METHODS AND MATERIALS: Using CBCT as reference, SGRT setup accuracy was examined based on 269 patients (415 treatments) treated with frameless cranial stereotactic radiosurgery (SRS) during 2018-2019. Patients were immobilized in customized head molds and open-face masks and monitored using OSI during treatment. The facial skin area in planning CT was used as OSI region of interest (ROI) for automatic surface alignment and the skull was used as the landmark for automatic CBCT/CT registration. A 6 degrees of freedom (6DOF) couch was used. Immediately after CBCT setup, an OSI verification image was captured, recording the SGRT setup differences. These differences were analyzed in 6DOFs and as a function of isocenter positions away from the anterior surface to assess OSI-ROI bias. The SGRT in-room setup time was estimated and compared with CBCT and orthogonal 2D kilovoltage (2DkV) setups. RESULTS: The SGRT setup difference (magnitude) is found to be 1.0 ± 2.5 mm and 0.1˚±1.4˚ on average among 415 treatments and within 5 mm/3˚ with greater than 95% confidence level (P < 0.001). Outliers were observed for very-posterior isocenters: 15 differences (3.6%) are >5.0mm and 9 (2.2%) are >3.0˚. The setup differences show minor correlations (|r| < 0.45) between translational and rotational DOFs and a minor increasing trend (<1.0 mm) in the anterior-to-posterior direction. The SGRT setup time is 0.8 ± 0.3 min, much shorter than CBCT (5 ± 2 min) and 2DkV (2 ± 1 min) setups. CONCLUSION: This study demonstrates that SGRT has sufficient accuracy for fast in-room patient setup and allows real-time motion monitoring for beam holding during treatment, potentially useful to guide radiotherapy of brain and nasopharynx cancer with standard fractionation.

A pilot study of 13N-ammonia cardiac PET imaging to assess subacute cardiotoxicity following adjuvant intensity-modulated radiotherapy for locally advanced breast cancer.

OBJECTIVE: (1) Assess the feasibility of 13 N-ammonia cardiac PET (13 N-ammonia-PET) imaging in radiotherapy (RT) treatment position in locally-advanced breast cancer (LABC) patients. (2) Correlate pre-/post-RT changes in myocardial flow reserve (MFR) with the corresponding radiation heart dose. METHODS: Ten left-sided LABC patients undergoing Volumetric Modulated-Arc-Therapy (VMAT) to chest wall and regional lymph nodes underwent a rest/stress 13 N-ammonia-PET at baseline and (median) 13 months post-RT. Changes in cardiac functions and coronary artery Ca2+ scoring between baseline and follow-up were correlated with average RT dose to the myocardium,3 coronary territories, and 17 myocardial segments. RESULTS: Eight (of 10) patients successfully completed the study. The average rest (stress) global MBF (ml.g-1.min-1) for baseline (follow-up) were 0.83 ± 0.25 (2.4 ± 0.79) and 0.92 ± 0.30 (2.76 ± 0.71), respectively. Differences in MBF, heart rate, blood pressure, and rate-pressure product (RPP) between baseline and follow-up were insignificant (P > 0.1).Strong (R = 0.79; P < 0.01) and moderate (R = 0.53; P = 0.37) correlation existed between MBF Rest and MBF Stress, and RPP respectively. Four patients showed a reduction in MFR of up to ~41% in follow-up studies, increasing to ~52% in myocardial segments close to high-radiation isodose lines in 5/8 patients. Agatston Ca + 2 scoring were zero in both baseline and follow-up in six patients; two patients exhibited mild increase in Ca + 2 on follow-ups (range:10-20).Rest and stress LVEF's were normal (>50) for all patients in both studies. CONCLUSION: The feasibility of 13 N-ammonia-PET imaging in treatment position of LABC patients was demonstrated. MFR at 1-year post-irradiation of the heart decreased in 50% of the patients. MFR may be a potential index for early detection of cardiotoxicity in BC patients receiving RT to the chest wall.

Implementation and validation of an in-house geometry optimization software for SRS VMAT planning of multiple cranial metastases.

PURPOSE: The implementation and evaluation of an in-house developed geometry optimization (GO) software are described. The GO script provides optimal lesion clustering, isocenter placement, and collimator angle of each arc for cranial multi-lesion stereotactic radiosurgery (SRS) volumetric modulated arc therapy (VMAT) planning. MATERIALS AND METHODS: An Eclipse-plugin program was developed to facilitate automatic plan geometry generation for multiple metastases SRS VMAT plans. A mixed, semi-supervised exhaustive and k-means clustering method is used to group lesions and place isocenters. The sum of squared euclidean distance (SSED) and the boundaries of lesions' projection from beams' eye view are used as supervised parameters to determine the optimal isocenter numbers. The collimator angle is optimized by minimizing the sum of the MLC opening area from all gantry angles for each arc. In all, 10 clinical cases treated during 2016-2017 were compared to plan quality of GO script generated plans. Paddick gradient index (GI), conformity index (CI), and local brain volume receiving 12 Gy (local V12 Gy) around each lesion were compared. RESULT: For four cases, the number of isocenters was reduced in the GO plans. For four other cases, the GO plans had the same number of isocenters as their corresponding clinical plans but with different lesion grouping. The GO plans had significantly lower GI (4.1 ± 1.0 vs 4.4 ± 0.9, P < 0.0001) and local V12 Gy (5.1 ± 4.2 vs 5.5 ± 4.3 in cm3 , P < 0.0001), but not significantly different mean normal brain dose or CI. The volume of normal brain receiving ≥6 Gy was significantly lower in the GO plans. The total time to run the GO script for each case was <2 min. CONCLUSION: The GO software automates lesion grouping, isocenter placement, and the collimator angles for SRS VMAT planning. When tested on 10 cases, the GO script resulted in improved plan quality and shorter planning time when compared to the clinical SRS VMAT plans.

A VMAT planning technique for locally advanced breast cancer patients with expander or implant reconstructions requiring comprehensive postmastectomy radiation therapy.

Locally advanced breast cancer patients with expander or implant reconstructions who require comprehensive postmastectomy radiotherapy (PMRT) can pose unique treatment planning challenges. Traditional 3D conformal radiation techniques often result in large dose inhomogeneity throughout the treatment volumes, inadequate target coverage, or excessive normal tissue doses. We have developed a volumetric modulated arc therapy (VMAT) planning technique without entering through the ipsilateral arm that produced adequate target volume coverage, excellent homogeneity throughout the target volume, and acceptable doses to the normal structures. Twenty left-sided and 10 right-sided patients with either ipsilateral or bilateral permanent implants or tissue expanders who received comprehensive PMRT between October 2014 and February 2016 were included in this study. Ten left-sided cases used deep inspiration breath hold (DIBH) technique, and others used free breathing (FB). Planning target volume (PTV) included chestwall, internal mammary nodes (IMNs), supraclavicular, and axillary lymph nodes. A VMAT plan using 4 or 5 partial arcs with 6 MV photon beam avoiding entering through the ipsilateral arm was generated for each patient. Prescription dose was 50 Gy in 25 fractions. PTV coverage, maximum depth of IMNs, dose homogeneity and dose to the heart, lungs, thyroid, contralateral intact breast or implant, liver, stomach, left anterior descending artery, ipsilateral brachial plexus, esophagus, spinal cord, and total MU were evaluated. PTV D95% (Gy) was 49.6 ± 0.9, 48.7 ± 0.9, and 49.5 ± 1.1; PTV D05% (Gy) was 55.7 ± 0.6, 55.1 ± 1.4, and 55.0 ± 0.7; maximum depth of IMNs (cm) was 4.3 ± 0.9, 4.6 ± 1.1, and 4.9 ± 2.3; ipsilateral lung, V20Gy (%) was 29.0 ± 2.1, 28.8 ± 2.5, and 27.5 ± 3.4; heart mean dose (Gy) was 4.2 ± 0.4, 7.5 ± 1.1, and 6.6 ± 0.8 for right-sided FB, left-sided FB, and left-sided DIBH cases, respectively. D95% of IMNs all received 100% prescription dose. The maximum dose (Gy) to the left anterior descending artery was 33.8 ± 11.7 for left-sided FB and 31.4 ± 7.3 for left-sided DIBH. VMAT technique avoiding ipsilateral arm can produce acceptable clinical plans for locally advanced breast cancer patients with expander or implant reconstructions receiving comprehensive PMRT.

Magnetic resonance spectroscopy imaging in radiotherapy planning for recurrent glioma.

PURPOSE: The purpose of this study was to investigate how incorporation of magnetic resonance spectroscopy imaging (MRSI) into radiotherapy planning would increase the target volume for patients with recurrent glioma. METHODS: After prior standard radiotherapy, 25 patients with recurrent glioma were treated with bevacizumab and concurrent hypofractionated stereotactic radiotherapy (HFSRT), delivering 30 Gy in five fractions. MRSI were acquired for 12 patients. Areas with markedly higher choline levels relative to the levels of total creatine and N-acetylaspartate were identified and referred to as MRSI voxels with elevated metabolite ratios (EMR). Gross tumor volume (GTV) consisted of contrast-enhancing tumor on T1-weighted magnetic resonance images (MRI) and computed tomography. Clinical target volume (CTV) was GTV + 5 mm margin and MRSI voxels with EMR. Overall survival (OS) and 6-month progression free survival (PFS) for these patients were reported in a prior publication [Gutin et al., Int. J. Radiat. Oncol., Biol., Phys. 75(1), 156-163 (2009)], and the outcome was correlated with the GTV and the volume of MRSI voxels with EMR in this study. RESULTS: Seven of the 12 patients had MRSI voxels with EMR. If none of the MRSI voxels with EMR were included, the CTV would range from 9.2 to 73.0 cm3 with a median of 31.0 cm3, whereas if all voxels were included, the CTV would range from 27.4 to 74.4 cm3 with a median of 35.0 cm3. For three of the seven patients, including the voxels with EMR, would have increased the CTV by 14%-23%. For one patient, where the MRSI voxels with EMR did not overlap the GTV, including these voxels would increase the CTV by 198%. No correlation could be found between the OS and PFS and the GTV or the volume of MRSI voxels with EMR. CONCLUSIONS: Seven of 12 patients with recurrent glioma had MRSI voxels with EMR. For four of these seven patients, including the MRSI voxels with EMR, significantly increased the CTV. This study does not have statistical power to conclude on the importance of including areas with MRSI-suspect disease into the radiation target volume.

Engineering lipid vesicles of enhanced intratumoral transport capabilities: correlating liposome characteristics with penetration into human prostate tumor spheroids.

Liposomes have been widely used delivery systems, particularly relevant to the development of cancer therapeutics. Numerous liposome-based drugs are in the clinic or in clinical trials today against multiple tumor types; however, systematic studies of liposome interactions with solid or metastatic tumor nodules are scarce. This study is describing the in vitro interaction between liposomes and avascular human prostate (LNCaP-LN3) tumor spheroids. The ability of fluorescently labelled liposomal delivery systems of varying physicochemical characteristics to penetrate within multicellular tumor spheroids has been investigated by confocal laser scanning microscopy. A variety of liposome characteristics and experimental parameters were investigated, including lipid bilayer composition, duration of liposome-spheroid interaction, mean liposome size, steric stabilization of liposomes. Electrostatic binding between cationic liposomes and spheroids was very efficient; however, it impeded any significant penetration of the vesicles within deeper layers of the tumor spheroid. Small unilamellar liposomes of neutral surface character did not bind as efficiently but exhibited enhanced penetrative transport capabilities closer to the tumor core. Polymer-coated (sterically stabilised) liposomes exhibited almost no interaction with the spheroid, indicating that their limited diffusion within avascular tissues may be a limiting step for their use against micrometastases. Multicellular tumor spheroids were used as models of solid tumor interstitium relevant to delivery systems able to extravasate from the microcapillaries or as models of prevascularized micrometastases. This study illustrates that interactions between liposomes and other drug delivery systems with multicellular tumor spheroids can offer critically important information with respect to optimizing solid or micrometastatic tumor delivery and targeting strategies.

Alpha-particle emitting atomic generator (Actinium-225)-labeled trastuzumab (herceptin) targeting of breast cancer spheroids: efficacy versus HER2/neu expression.

PURPOSE: The humanized monoclonal antibody, trastuzumab (Herceptin), directed against HER2/neu, has been effective in the treatment of breast cancer malignancies. However, clinical activity has depended on HER2/neu expression. Radiolabeled trastuzumab has been considered previously as a potential agent for radioimmunotherapy. The objective of this study was to investigate the efficacy of trastuzumab labeled with the alpha-particle emitting atomic generator, actinium-225 ((225)Ac), against breast cancer spheroids with different HER2/neu expression levels. (225)Ac has a 10-day half-life and a decay scheme yielding four alpha-particles. EXPERIMENTAL DESIGN: The breast carcinoma cell lines MCF7, MDA-MB-361 (MDA), and BT-474 (BT) with relative HER2/neu expression (by flow cytometry) of 1:4:18 were used. Spheroids of these cell lines were incubated with different concentrations of (225)Ac-trastuzumab, and spheroid growth was measured by light microscopy over a 50-day period. RESULTS: The activity concentration required to yield a 50% reduction in spheroid volume at day 35 was 18.1, 1.9, and 0.6 kBq/ml (490, 52, 14 nCi/ml) for MCF7, MDA, and BT spheroids, respectively. MCF7 spheroids continued growing but with a 20-30 day growth delay at 18.5 kBq/ml. MDA spheroid growth was delayed by 30-40 days at 3.7 kBq/ml; at 18.5 kBq/ml, 12 of 12 spheroids disaggregated after 70, days and cells remaining from each spheroid failed to form colonies within 2 weeks of being transferred to adherent dishes. Eight of 10 BT spheroids failed to regrow at 1.85 kBq/ml. All of the BT spheroids at activity concentrations 3.7 kBq/ml failed to regrow and to form colonies. The radiosensitivity of these three lines as spheroids was evaluated as the activity concentration required to reduce the treated to untreated spheroid volume ratio to 0.37, denoted DVR(37). An external beam radiosensitivity of 2 Gy was found for spheroids of all three of the cell lines. After alpha-particle irradiation a DVR(37) of 1.5, 3.0, and 2.0 kBq/ml was determined for MCF7, MDA, and BT, respectively. CONCLUSION: These studies suggest that (225)Ac-labeled trastuzumab may be a potent therapeutic agent against metastatic breast cancer cells exhibiting intermediate to high HER2/neu expression.

Combination treatment with 17-N-allylamino-17-demethoxy geldanamycin and acute irradiation produces supra-additive growth suppression in human prostate carcinoma spheroids.

Failure to control localized prostate cancer can result not only in localized disease progression but also distant metastatic spread. Whereas significant advances in both surgical technique and radiation therapy have improved local control rates with decreased morbidity, consistent long-term control remains elusive. This study investigates the potential of 17-N-allylamino-17-demethoxy geldanamycin (17AAG), a geldanamycin derivative, to sensitize tumor cells to ionizing radiation, permitting a significant improvement to targeted radiotherapies of prostate carcinoma. As a monotherapeutic, 17AAG functions to modulate the action of heat shock protein 90, ultimately affecting a multitude of cellular signaling pathways. It is in Phase I trial and has shown promise in controlling prostate cancer progression. Human prostate tumor cells (LNCaP and CWR22Rv1) were grown as spheroids and incubated for 96 h with increasing doses of 17AAG immediately before and after 2 or 6 Gy low linear energy transfer (LET), high dose-rate irradiation (Cs-137 irradiator). Twelve or 24 spheroids (initial diameter, 150-200 microm) were used per experiment. Response was determined by spheroid volume measurements taken over at least 40 days, after treatment. Incubation of either cell line with 17AAG (

Patient-specific, 3-dimensional dosimetry in non-Hodgkin's lymphoma patients treated with 131I-anti-B1 antibody: assessment of tumor dose-response.

UNLABELLED: A comprehensive, SPECT-based, patient-specific 3-dimensional (3D) dosimetry analysis has been performed using 3D-ID, a previously developed software package. The role of the total-body tumor burden, individual lesion size, tumor absorbed dose, and the spatial distribution of the absorbed dose on response and on the time course of tumor shrinkage has been examined in patients with lymphoma treated by radioimmunotherapy. METHODS: Data from 15 patients participating in a phase II study of (131)I-labeled anti-B1 antibody (tositumomab) were used. Patients were administered a tracer dose of (131)I for imaging and pharmacokinetics. Dose estimates from the tracer studies were used to prescribe the therapeutic administration such that the whole-body absorbed dose did not exceed 75 cGy. All patients received a fixed mass amount of antibody for both the tracer and the therapeutic administrations. SPECT and planar imaging were performed 3-4 d after the therapeutic administration. CT or MRI scans were available on all patients. Total tumor burden was assessed by drawing contours around all lymphoma lesions identified on whole-body CT or MRI. Mean absorbed doses were estimated for selected, index lesions by conventional dosimetry and also by 3D SPECT-based dosimetry. Using a patient-specific dosimetry package, 3D-ID, dose-volume histograms were also generated to assess the spatial distribution of absorbed dose. This approach made it possible to obtain estimates of the minimum and maximum absorbed doses for individual tumors in addition to the mean. RESULTS: Mean absorbed dose estimates obtained by patient-specific SPECT-based dosimetry using 3D-ID were within 2%-5% of estimates obtained by conventional dosimetry. None of the absorbed dose parameters (mean, minimum, maximum, uniformity) were found to have a significant correlation with tumor response. The total-body tumor burden did not impact on overall response or toxicity. CONCLUSION: This analysis represents the first full reported implementation of a patient-specific 3D dosimetry package. The absence of a dose-response relationship for tumors is surprising and suggests that absorbed dose is not the sole determinant of tumor response in these patients. The absence of a correlation between the total-body tumor burden and overall response or toxicity suggests that tailoring the milligram amount of administered antibody to patient tumor burden is not likely to improve response or reduce toxicity.

Targeted alpha particle immunotherapy for myeloid leukemia.

Unlike beta particle-emitting isotopes, alpha emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the beta-emitters (131)I and (90)Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of beta-emitting constructs, the alpha-emitting isotope (213)Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg (213)Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the (213)Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with beta-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of (213)Bi-HuM195, and it is the first proof-of-concept for systemic targeted alpha particle immunotherapy in humans.