Publications by authors named "Jeffrey Y C Wong"

80 Publications

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

Diagnostic Performance of F-DCFPyL-PET/CT in Men with Biochemically Recurrent Prostate Cancer: Results from the CONDOR Phase III, Multicenter Study.

Clin Cancer Res 2021 Jul 23;27(13):3674-3682. Epub 2021 Feb 23.

University of California San Francisco, San Francisco, California.

Purpose: Current FDA-approved imaging modalities are inadequate for localizing prostate cancer biochemical recurrence (BCR). F-DCFPyL is a highly selective, small-molecule prostate-specific membrane antigen-targeted PET radiotracer. CONDOR was a prospective study designed to determine the performance of F-DCFPyL-PET/CT in patients with BCR and uninformative standard imaging.

Experimental Design: Men with rising PSA ≥0.2 ng/mL after prostatectomy or ≥2 ng/mL above nadir after radiotherapy were eligible. The primary endpoint was correct localization rate (CLR), defined as positive predictive value with an additional requirement of anatomic lesion colocalization between F-DCFPyL-PET/CT and a composite standard of truth (SOT). The SOT consisted of, in descending priority (i) histopathology, (ii) subsequent correlative imaging findings, or (iii) post-radiation PSA response. The trial was considered a success if the lower bound of the 95% confidence interval (CI) for CLR exceeded 20% for two of three F-DCFPyL-PET/CT readers. Secondary endpoints included change in intended management and safety.

Results: A total of 208 men with a median baseline PSA of 0.8 ng/mL (range: 0.2-98.4 ng/mL) underwent F-DCFPyL-PET/CT. The CLR was 84.8%-87.0% (lower bound of 95% CI: 77.8-80.4). A total of 63.9% of evaluable patients had a change in intended management after F-DCFPyL-PET/CT. The disease detection rate was 59% to 66% (at least one lesion detected per patient by F-DCFPyL-PET/CT by central readers).

Conclusions: Performance of F-DCFPyL-PET/CT achieved the study's primary endpoint, demonstrating disease localization in the setting of negative standard imaging and providing clinically meaningful and actionable information. These data further support the utility of F-DCFPyL-PET/CT to localize disease in men with recurrent prostate cancer..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4573DOI Listing
July 2021

Comparative evaluation of treatment plan quality for a prototype biology-guided radiotherapy system in the treatment of nasopharyngeal carcinoma.

Med Dosim 2021 Summer;46(2):171-178. Epub 2020 Nov 30.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, USA.

We aimed to compare prototype treatment plans for a new biology-guided radiotherapy (BgRT) machine in its intensity-modulated radiation therapy (IMRT) mode with those using existing IMRT delivery techniques in treatment of nasopharyngeal carcinoma (NPC). We retrospectively selected ten previous NPC patients treated in 33 fractions according to the NRG-HN001 treatment protocol. Three treatment plans were generated for each patient: a helical tomotherapy (HT) plan with a 2.5-cm jaw, a volumetric modulated arc therapy (VMAT) plan using 2 to 4 6-MV arc fields, and a prototype IMRT plan for a new BgRT system which uses a 6-MV photon beam on a ring gantry that rotates at 60 rotations per minute with a couch that moves in small incremental steps. Treatment plans were compared using dosimetric parameters to planning target volumes (PTVs) and organs at risk (OARs) as specified by the NRG-HN001 protocol. Plans for the three modalities had comparable dose coverage, mean dose, and dose heterogeneity to the primary PTV, while the prototype IMRT plans had greater dose heterogeneity to the non-primary PTVs, with the average homogeneity index ranging from 1.28 to 1.50 in the prototype plans. Six of all the 7 OAR mean dose parameters were lower with statistical significance in the prototype plans compared to the HT and VMAT plans with the other mean dose parameter being comparable, and all the 18 OAR maximum dose parameters were comparable or lower with statistical significance in the prototype plans. The average left and right parotid mean doses in the prototype plans were 10.5 Gy and 10.4 Gy lower than those in the HT plans, respectively, and were 5.1 Gy and 5.2 Gy lower than those in the VMAT plans, respectively. Compared to that with the HT and VMAT plans, the treatment time was longer with statistical significance with the prototype IMRT plans. Based on dosimetric comparison of ten NPC cases, the prototype IMRT plans achieved comparable or better critical organ sparing compared to the HT and VMAT plans for definitive NPC radiotherapy. However, there was higher dose heterogeneity to non-primary targets and longer estimated treatment time with the prototype plans.
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http://dx.doi.org/10.1016/j.meddos.2020.11.002DOI Listing
November 2020

In Reply to Scarpelli et al.

Int J Radiat Oncol Biol Phys 2020 12 18;108(5):1396. Epub 2020 Nov 18.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

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http://dx.doi.org/10.1016/j.ijrobp.2020.07.2315DOI Listing
December 2020

Total marrow and total lymphoid irradiation in bone marrow transplantation for acute leukaemia.

Lancet Oncol 2020 10;21(10):e477-e487

Department of Radiotherapy and Radiosurgery, Humanitas Clinical and Research Hospital-IRCCS, Rozzano, Milan, Italy.

The use of total body irradiation as part of conditioning regimens for acute leukaemia is progressively declining because of concerns of late toxic effects and the introduction of radiation-free regimens. Total marrow irradiation and total marrow and lymphoid irradiation represent more targeted forms of radiotherapy compared with total body irradiation that have the potential to decrease toxicity and escalate the dose to the bone marrow for high-risk patients. We review the technological basis and the clinical development of total marrow irradiation and total marrow and lymphoid irradiation, highlighting both the possible advantages as well as the current roadblocks for widespread implementation among transplantation units. The exact role of total marrow irradiation or total marrow and lymphoid irradiation in new conditioning regimens seems dependent on its technological implementation, aiming to make the whole procedure less time consuming, more streamlined, and easier to integrate into the clinical workflow. We also foresee a role for computer-assisted planning, as a way to improve planning and delivery and to incorporate total marrow irradiation and total marrow and lymphoid irradiation in multi-centric phase 2-3 trials.
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http://dx.doi.org/10.1016/S1470-2045(20)30342-9DOI Listing
October 2020

TAG-72-Targeted α-Radionuclide Therapy of Ovarian Cancer Using Ac-Labeled DOTAylated-huCC49 Antibody.

J Nucl Med 2021 01 3;62(1):55-61. Epub 2020 Jul 3.

Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, California

Radioimmunotherapy, an approach using radiolabeled antibodies, has had minimal success in the clinic with several β-emitting radionuclides for the treatment of ovarian cancer. Alternatively, radioimmunotherapy with α-emitters offers the advantage of depositing much higher energy over shorter distances but was thought to be inappropriate for the treatment of solid tumors, for which antibody penetration is limited to a few cell diameters around the vascular system. However, the deposition of high-energy α-emitters to tumor markers adjacent to a typical leaky tumor vascular system may have large antitumor effects at the tumor vascular level, and their reduced penetration in normal tissue would be expected to lower off-target toxicity. To evaluate this concept, DOTAylated-huCC49 was labeled with the α-emitter Ac to target tumor-associated glycoprotein 72-positive xenografts in a murine model of ovarian cancer. Ac-labeled DOTAylated-huCC49 radioimmunotherapy significantly reduced tumor growth in a dose-dependent manner (1.85, 3.7, and 7.4 kBq), with the 7.4-kBq dose extending survival by more than 3-fold compared with the untreated control. Additionally, a multitreatment regime (1.85 kBq followed by 5 weekly doses of 0.70 kBq for a total of 5.4 kBq) extended survival almost 3-fold compared with the untreated control group, without significant off-target toxicity. These results establish the potential for antibody-targeted α-radionuclide therapy for ovarian cancer, which may be generalized to α-radioimmunotherapy in other solid tumors.
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http://dx.doi.org/10.2967/jnumed.120.243394DOI Listing
January 2021

Estimation of radiation-induced, organ-specific, secondary solid-tumor occurrence rates with total body irradiation and total marrow irradiation treatments.

Pract Radiat Oncol 2020 Sep - Oct;10(5):e406-e414. Epub 2020 Apr 14.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California.

Purpose: We aimed to predict and compare radiation-induced, organ-specific, secondary solid-tumor occurrence risks from conventional total body irradiation (TBI) and total marrow irradiation (TMI) for patients undergoing hematopoietic cell transplant.

Methods And Materials: We retrospectively selected 20 patients who received TMI treatments before hematopoietic cell transplant. Ten patients (5 men; 5 women) received 12 Gy to the skeletal bones, lymph nodes, and spleen, and the other 10 patients (5 men; 5 women) received an escalated dose of 20 Gy to the same targets and 12 Gy to the brain and liver. A conventional TBI treatment plan was generated for each patient with a prescription dose of 12 Gy, using anterior-posterior and posterior-anterior photon beams with lung shielding and a chest wall boost with electron beams. Secondary cancer risks were estimated using linear-exponential and plateau models for major organs.

Results: At the 12 Gy dose level, using the linear-exponential model, the total radiation-induced secondary solid-tumor risks for major organs were 159.3 ± 8.7 for men and 221.5 ± 14.4 for women per 10,000 people per year with the TMI plans, which is a reduction of 38.8% and 32.9%, respectively, compared with those with the TBI plans. At the 20 Gy dose level, the risks were 220.3 ± 8.3 for men and 298.5 ± 9.3 for women with the TMI plans, which is a reduction of 14.6% and 9.2%, respectively, compared with those with the 12 Gy TBI plans. Significant risk reductions were also found with the TMI plans using the plateau risk model.

Conclusions: At both the 12 Gy and 20 Gy prescription dose levels, a conditioning regimen using TMI could significantly lower overall radiation-induced secondary solid-tumor risks for major organs compared with a conditioning regimen with standard 12 Gy TBI. Clinical data from long-term follow-up studies are needed to verify the model predictions.
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http://dx.doi.org/10.1016/j.prro.2020.03.006DOI Listing
April 2020

Residual setup errors in cranial stereotactic radiosurgery without six degree of freedom robotic couch: Frameless versus rigid immobilization systems.

J Appl Clin Med Phys 2020 Mar 18;21(3):87-93. Epub 2020 Feb 18.

City of Hope National Medical Center, Duarte, CA, USA.

Purpose And Objectives: This IRB-approved study was to compare the residual inter-fractional setup errors and intra-fractional motion of patients treated with cranial stereotactic radiosurgery without a 6 degree of freedom (DoF) couch. We evaluated both frameless non-invasive vacuum-suction immobilization (Aktina PinPoint) and TALON rigid screw immobilization.

Materials And Methods: Twenty consecutive patients treated by Varian TrueBeam STX or Tomotherapy were selected for data collection. The dose and number of fractions received by each patient ranged from 18 Gy in 1 fraction (SRS) to 25 Gy in 5 fractions (SRT). Twelve patients were immobilized using PinPoint, a frameless suction system (Aktina Medical, New York) and eight patients were immobilized using the TALON rigid screw system. Customized head cushions were used for all patients. Six Atkina patients received pre- and post-treatment cone-beam CT (CBCT) to evaluate the intra-fractional motion of the Aktina system. The intra-fractional motion with the TALON rigid screw system has been reported to be negligible and was not repeated in this study. All patients received pre-treatment CBCT or megavoltage CT (MVCT) to assess inter-fractional setup accuracy. Shifts to the final treatment position were determined based on matching bony anatomy in the pre-treatment setup CT and the planning CT. Setup CT and planning CT were registered retrospectively based on bony anatomy using image registration software to quantify rotational and translational errors.

Results: For the frameless Aktina system, mean and standard deviation of the intra-fractional motion were -0.5 ± 0.7 mm (lateral), 0.1 ± 0.9 mm (vertical), -0.5 ± 0.6 mm (longitudinal), -0.04 ± 0.18°(pitch), -0.1 ± 0.23°(yaw), and -0.03 ± 0.17°(roll) indicating negligible intra-fractional motion. Inter-fractional rotation errors were -0.10 ± 0.25° (pitch), -0.08 ± 0.16° (yaw), and -0.20 ± 0.41° (roll) for TALON rigid screw immobilization versus 0.20 ± 0.69° (pitch), 0.34 ± 0.56° (yaw), 0.35 ± 0.82° (roll) for frameless vacuum-suction immobilization showing that the rigid immobilization setup is more reproducible than the frameless immobilization. Without rotational correction by a 6 DoF couch, residual registration error exists and increases with distance from the image fusion center. In a 3D vector space, a tumor located 5 cm from the center of image fusion would require a 0.9 mm margin with the TALON system and a 2.1 mm margin with Aktina.

Conclusions: With image-guided radiotherapy, translational setup errors can be corrected by image registration between pre-treatment setup CT and planning CT. However, rotational errors cannot be accounted for without a 6 DoF couch. Our study showed that the frameless Aktina immobilization system provided negligible intra-fractional motion. The inter-fractional rotation setup error using Aktina was larger than rigid immobilization with the TALON system. To treat a single lesion far from the center of image registration or for multiple lesions in a single plan, additional margin may be needed to account for the uncorrectable rotational setup errors.
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http://dx.doi.org/10.1002/acm2.12828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075371PMC
March 2020

Antibody Targeted PET Imaging of Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA Positive Tumors.

Bioconjug Chem 2020 03 30;31(3):743-753. Epub 2020 Jan 30.

Department of Molecular Imaging and Therapy, Beckman Research Institute, City of Hope, Duarte, California 91010, United States.

Lipid nanodiscs (LNDs), comprising a phospholipid bilayer encircled by two molecules of a recombinant membrane scaffold protein, can be targeted to tumors with covalently attached antibodies (Abs) or their fragments. Antibody attachment to click chemistry based PEGylated lipids on LNDs including DOTA allowed PET imaging with the positron emitter Cu. Carcinoembryonic antigen (CEA) positive tumors in CEA transgenic mice were chosen as a tumor target. Fab' fragments, that otherwise are rapidly cleared by the kidney due to their small size, were retained in circulation when conjugated to LNDs. Untargeted PET imaging of Cu-DOTA-LNDs revealed low tumor uptake (4-5% ID/g) in the range expected for the enhanced permeability retention (EPR) effect with high liver uptake (17-21% ID/g) indicating gut clearance. Fab' targeted LNDs showed little improvement over untargeted LNDs, but intact IgG targeted LNDs gave high tumor uptake (40% ID/g) with low liver (8% ID/g), demonstrating that tumor targeting with antibody conjugated LNDs is feasible.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00854DOI Listing
March 2020

Phase I Study of Yttrium-90 Radiolabeled M5A Anti-Carcinoembryonic Antigen Humanized Antibody in Patients with Advanced Carcinoembryonic Antigen Producing Malignancies.

Cancer Biother Radiopharm 2020 Feb 7;35(1):10-15. Epub 2020 Jan 7.

Department of Radiation Oncology, City of Hope National Cancer Center, Duarte, California.

M5A is a humanized monoclonal antibody (mAb) directed against carcinoembryonic antigen (CEA) The purpose of this first in human phase I dose-escalation trial was to characterize the toxicities and determine the maximum tolerated dose (MTD) of yttrium-90 (Y)-DOTA-M5A as a single agent and in combination with gemcitabine (gem). Patients with advanced metastatic CEA-producing malignancies who had progressed on standard therapies were first administered indium-111 (In)-DOTA-M5A. If tumor targeting was observed, the patient then received the therapy dose of Y-DOTA-M5A. Serial scans, blood sampling, and 24 h urine collections were then performed to estimate radiation doses to organs and total body. Assays for human antihuman antibody (HAHA) responses were performed out to 6 months. Of the 18 patients who received In-DOTA-M5A, 16 received Y-DOTA-M5A therapy; 1 patient at 14 mCi/m with gem (150 mg/m days 1and 3), 3 patients at 12 mCi/m with gem, 6 patients at 12 mCi/m without gem, and 6 at 10 mCi/m without gem. Prolonged cytopenias resulted in discontinuation of dose escalation with gemcitabine. A single agent MTD of 10 mCi/m was established based on dose-limiting hematopoietic toxicities. HAHA immune response was identified in 2 of 16 patients (12.5%). Stable disease at 3 months was seen in 10 patients and 2 patients demonstrated an 88% and 64% decrease in CEA back to normal levels. In 2 patients In-DOTA-M5A imaging revealed previously unknown brain metastases. This study demonstrates the potential utility of the Y-DOTA-M5A anti-CEA mAb as a therapeutic antibody. There is decreased immunogenicity compared with murine and chimeric mAbs, allowing for the potential of multiple administrations. Combined modality therapy approaches incorporating this agent should continue to be evaluated.
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http://dx.doi.org/10.1089/cbr.2019.2992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044770PMC
February 2020

ImmunoPET, [Cu]Cu-DOTA-Anti-CD33 PET-CT, Imaging of an AML Xenograft Model.

Clin Cancer Res 2019 12 23;25(24):7463-7474. Epub 2019 Sep 23.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California.

Purpose: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia, which results in poor survival outcomes. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). There is currently no AML-specific noninvasive imaging method to detect disease, including in extramedullary organs, representing an unmet clinical need. About 85% to 90% of human myeloid leukemia cells express CD33 cell surface receptors, highlighting CD33 as an ideal candidate for AML immunoPET.

Experimental Design: We evaluated whether [Cu]Cu-DOTA-anti-CD33 murine mAb can be used for immunoPET imaging of AML in a preclinical model. MicroCT was adjusted to detect spatial/anatomical details of PET activity. For translational purposes, a humanized anti-CD33 antibody was produced; we confirmed its ability to detect disease and its distribution. We reconfirmed/validated CD33 antibody-specific targeting with an antibody-drug conjugate (ADC) and radioimmunotherapy (RIT).

Results: [Cu]Cu-DOTA-anti-CD33-based PET-CT imaging detected CD33 AML in mice with high sensitivity (95.65%) and specificity (100%). The CD33 PET activity was significantly higher in specific skeletal niches [femur ( < 0.00001), tibia ( = 0.0001), humerus ( = 0.0014), and lumber spine ( < 0.00001)] in AML-bearing mice (over nonleukemic control mice). Interestingly, the hybrid PET-CT imaging showed high disease activity in the epiphysis/metaphysis of the femur, indicating regional spatial heterogeneity. Anti-CD33 therapy using newly developed humanized anti-CD33 mAb as an ADC ( = 0.02) and [Ac]Ac-anti-CD33-RIT ( < 0.00001) significantly reduced disease burden over that of respective controls.

Conclusions: We have successfully developed a novel anti-CD33 immunoPET-CT-based noninvasive modality for AML and its spatial distribution, indicating a preferential skeletal niche.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911626PMC
December 2019

Multi-institutional evaluation of MVCT guided patient registration and dosimetric precision in total marrow irradiation: A global health initiative by the international consortium of total marrow irradiation.

Radiother Oncol 2019 12 14;141:275-282. Epub 2019 Aug 14.

Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, USA. Electronic address:

Purpose: Total marrow irradiation (TMI) is a highly conformal treatment of the human skeleton structure requiring a high degree of precision and accuracy for treatment delivery. Although many centers worldwide initiated clinical studies using TMI, currently there is no standard for pretreatment patient setup. To this end, the accuracy of different patient setups was measured using pretreatment imaging. Their impact on dose delivery was assessed for multiple institutions.

Methods And Materials: Whole body imaging (WBI) or partial body imaging (PBI) was performed using pretreatment megavoltage computed tomography (MVCT) in a helical Tomotherapy machine. Rigid registration of MVCT and planning kilovoltage computed tomography images were performed to measure setup error and its effect on dose distribution. The entire skeleton was considered the planning target volume (PTV) with five sub regions: head/neck (HN), spine, shoulder and clavicle (SC), and one avoidance structure, the lungs. Sixty-eight total patients (>300 images) across six institutions were analyzed.

Results: Patient setup techniques differed between centers, creating variations in dose delivery. Registration accuracy varied by anatomical region and by imaging technique, with the lowest to the highest degree of pretreatment rigid shifts in the following order: spine, pelvis, HN, SC, and lungs. Mean fractional dose was affected in regions of high registration mismatch, in particular the lungs.

Conclusions: MVCT imaging and whole body patient immobilization was essential for assessing treatment setup, allowing for the complete analysis of 3D dose distribution in the PTV and lungs (or avoidance structures).
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http://dx.doi.org/10.1016/j.radonc.2019.07.010DOI Listing
December 2019

Radiation-Related Toxicities Using Organ Sparing Total Marrow Irradiation Transplant Conditioning Regimens.

Int J Radiat Oncol Biol Phys 2019 12 14;105(5):1025-1033. Epub 2019 Aug 14.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California. Electronic address:

Purpose: Toxicities after organ sparing myeloablative total marrow irradiation (TMI) conditioning regimens have not been well characterized. The purpose of this study is to report pulmonary, renal, thyroid, and cataract toxicities from a prospective trial monitoring patients up to 8 years after TMI.

Methods And Materials: A total of 142 patients with primarily multiple myeloma or acute leukemia undergoing hematopoietic cell transplantation were evaluated. Follow-up included pulmonary function tests, serum creatinine, glomerular filtration rate, thyroid panel, and ophthalmologic examinations performed at 100 days, 6 months, and annually. Median TMI dose was 14 Gy (10-19 Gy) delivered at 1.5 to 2.0 Gy twice per day at a dose-rate of 200 cGy/min.

Results: Median age was 52 years (range 9-70). Median follow-up (range) for all patients was 2 years (0-8) and for patients alive at the time of last follow-up (n = 50), 5.5 years (0-8). Mean organ doses in Gy were lung 7.0, kidneys 7.1, thyroid 6.7, and lens 2.8. The crude incidence of radiation pneumonitis (RP) was 1 of 142 (0.7%). The cumulative incidence of infection and RP (I/RP) was 22.7% at 2 years post-TMI. Mean lung dose ≤8 Gy predicted for significantly lower rates of I/RP (2-year cumulative incidence 20.8% vs 31.8%, P = .012). No radiation-induced renal toxicity was noted. Hypothyroidism occurred in 6.0% and cataract formation in 7.0% of patients.

Conclusions: TMI delivered with intensity modulated radiation therapy results in lower organ doses and was associated with fewer toxicities compared with historical cohorts treated with conventional total body irradiation. Keeping the mean lung dose to 8 Gy or less was associated with lower pulmonary complications. Further evaluation in clinical trials of intensity modulated radiation therapy to deliver TMI, total marrow and lymphoid irradiation, and organ sparing conformal total body irradiation is warranted.
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http://dx.doi.org/10.1016/j.ijrobp.2019.08.010DOI Listing
December 2019

Randomized phase II trial of sipuleucel-T immunotherapy preceded by sensitizing radiation therapy and sipuleucel-T alone in patients with metastatic castrate resistant prostate cancer.

Cancer Treat Res Commun 2019 20;19:100116. Epub 2018 Dec 20.

Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States.

Background: Sipuleucel-T is an autologous cellular immunotherapy indicated for patients with asymptomatic or minimally symptomatic metastatic castration resistant prostate cancer (mCRPC). Since radiation therapy (RT) can suppress bone marrow function and immune responses, previous studies evaluating sipuleucel-T excluded patients who received RT less than or equal to 28 days prior to sipuleucel-T therapy. Recent evidence suggests that RT may act synergistically with immunotherapy to enhance and broaden antitumor immune response.

Methods: Patients who met standard criteria for sipuleucel-T were randomized to receive sipuleucel-T alone (Arm A) or sipuleucel-T initiated 1 week after completing sensitizing RT to single metastatic site (Arm B). RT was delivered at 300cGy/day to 3000 cGy total. The primary endpoint was the ability to safely combine sipuleucel-T preceded by RT and generate sipuleucel-T with adequate product immune activation parameters. Secondary endpoints included the measurement of systemic immune responses to prostatic acid phosphatase (PAP), a target for sipuleucel-T immune therapy and PA20204 (recombinant fusion protein utilized in the generation of sipuleucel-T).

Results: 51 pts were enrolled, 2 did not receive any sipuleucel-T because of vascular access problems and were excluded. 24 were treated on Arm A, 25 on Arm B. 47/49 patients received all 3 sipuleucel-T infusions. Median age was 66 yrs (range 45-90). Sipuleucel-T product parameters including: total nucleated cell (TNC) count, antigen presenting cell (APC) count were similar in both groups. Cumulative APC upregulation was higher in Arm A. 1 patient in Arm A demonstrated PSA response. Median progression free survival (PFS) was 2.46 months on Arm A and 3.65 months on Arm B (p = 0.06). Both arms showed similar increases in humoral responses to PA2024 and PAP. IFN-ƴ ELISPOT T-cell activation responses to PA20204 were observed in both arms, but were more robust in the Arm A (p = 0.028). Both arms were well-tolerated, with fatigue as the most common grade 2 adverse event (1 patient in Arm A and 3 patients in Arm B).

Conclusions: Sensitizing RT completed 1 week before generation of sipuleucel-T did not affect the majority of product parameters and the ability to deliver sipuleucel-T therapy. RT did not enhance the humoral and cellular responses associated with sipuleucel-T therapy.
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http://dx.doi.org/10.1016/j.ctarc.2018.100116DOI Listing
September 2019

Prototype Small-Animal PET-CT Imaging System for Image-guided Radiation Therapy.

IEEE Access 2019 30;7:143207-143216. Epub 2019 Sep 30.

Department of Radiation Oncology, City of Hope, Duarte, CA 91010, USA.

Molecular imaging is becoming essential for precision targeted radiation therapy, yet progress is hindered from a lack of integrated imaging and treatment systems. We report the development of a prototype positron emission tomography (PET) scanner integrated into a commercial cone beam computed tomography (CBCT) based small animal irradiation system for molecular-image-guided, targeted external beam radiation therapy. The PET component consists of two rotating Hamamatsu time-of-flight PET modules positioned with a bore diameter of 101.6 mm and a radial field-of-view of 53.1 mm. The measured energy resolution after linearity correction at 511 KeV was 12.9% and the timing resolution was 283.6 ps. The measured spatial resolutions at the field-of-view center and 5 mm off the radial center were 2.6 mm × 2.6 mm × 1.6 mm and 2.6 mm × 2.6 mm × 2.7 mm respectively. F-Fluorodeoxyglucose-based PET imaging of a NEMA NU 4-2008 phantom resolved cylindrical volumes with diameters as small as 3 mm. To validate the system in-vivo, we performed Cu-DOTA-M5A PET and computed tomography (CT) imaging of carcinoembryonic antigen (CEA)-positive colorectal cancer in athymic nude mice and compared the results with a commercially available Siemens Inveon PET/CT system. The prototype PET system performed comparably to the Siemens system for identifying the location, size, and shape of tumors. Regions of heterogeneous Cu-DOTA-M5A uptake were observed. Using Cu-DOTA-M5A PET and CT images, a Monte Carlo-based radiation treatment plan was created to escalate the dose to the Cu-DOTA-M5A-based, highly active, biological target volume while largely sparing the normal tissue. Results demonstrate the feasibility of molecular-image-guided treatment plans using the prototype theranostic system.
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http://dx.doi.org/10.1109/access.2019.2944683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239319PMC
September 2019

Total Body Irradiation: Guidelines from the International Lymphoma Radiation Oncology Group (ILROG).

Int J Radiat Oncol Biol Phys 2018 07 2;101(3):521-529. Epub 2018 May 2.

Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Total body irradiation (TBI) remains an effective myeloablative treatment in regimens used for preparation and conditioning before allogeneic stem cell transplantation for leukemia. The regimens used vary across institutions in terms of dose, dose rate, fractionation, and technique. The objective of this document is to provide comprehensive guidelines for the current practice of delivering total body irradiation.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.071DOI Listing
July 2018

Outcomes and toxicity of 313 prostate cancer patients receiving helical tomotherapy after radical prostatectomy.

Adv Radiat Oncol 2017 Oct-Dec;2(4):597-607. Epub 2017 Aug 8.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California.

Purpose: There are limited long-term data on patients treated with image guided intensity modulated radiation therapy (IG-IMRT) for prostate cancer recurrence or high-risk disease features after radical prostatectomy. We report single-institution results for patients treated with IG-IMRT and identify variables associated with outcome.

Methods And Materials: This is a retrospective chart review consisting of 313 consecutive patients who were treated with adjuvant or salvage IG-IMRT from 2004 to 2013. Cox proportional hazards analysis was used to identify factors related to survival and toxicity. Toxicity was graded using the Common Terminology Criteria for Adverse Events Version 4.0.

Results: The median follow-up was 55 months (range, 6-131 months). The median pre-radiation therapy (RT) prostate-specific antigen (PSA) was 0.3 ng/mL (range, <0.01-55.4). The vast majority of patients (87%) received elective pelvic nodal irradiation (median dose: 45 Gy). Androgen deprivation therapy (ADT) was given to 39% of patients for a median of 9 months. Five-year biochemical progression-free survival and distant metastasis-free survival were 59% (95% confidence interval, 53%-66%) and 89% (95% confidence interval, 85%-93%), respectively. On multivariate analysis, higher pre-RT PSA (>0.2 ng/mL), biopsy Gleason score (≥7 [4+3]), and duration of ADT (>6 months) were significantly associated ( < .05) with biochemical progression-free survival. Actuarial late grade 3 genitourinary and gastrointestinal toxicities at 5 years were 10% and 2%, respectively.

Conclusion: Our results suggest that lower pre-RT PSA level and longer duration of ADT are associated with improved biochemical control. The incidence of late grade 3 gastrointestinal toxicity was low, but late grade 3 genitourinary toxicity was higher than anticipated.
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http://dx.doi.org/10.1016/j.adro.2017.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707427PMC
August 2017

US Intergroup Study of Chemotherapy Plus Dasatinib and Allogeneic Stem Cell Transplant in Philadelphia Chromosome Positive ALL.

Blood Adv 2016 Dec;1(3):250-259

Fred Hutchinson Cancer Research Center, Seattle, WA.

This multicenter trial was conducted to determine whether the addition of dasatinib to chemotherapy followed by an allogeneic hematopoietic cell transplant (HCT) in patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) was feasible. Patients ≥ 18 and ≤ 60 years of age with newly diagnosed Ph+ ALL received up to 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate with dasatinib. Patients with an available matched sibling or unrelated donor underwent an allogeneic HCT in first complete remission (CR1) followed by daily dasatinib starting from day 100. Others received maintenance therapy with vincristine and prednisone for 2 years and dasatinib indefinitely. 97 patients (94 evaluable) with median age of 44 years (range, 20 - 60) and median WBC at presentation of 10 × 10/L (range, 1 - 410 × 10/L) were accrued. 83 (88%) patients achieved CR or CR with incomplete count recovery (CRi) and 41 underwent ASCT in CR1. Median follow-up is 36 months (range, 9 - 63). For the overall population, overall survival (OS), event-free survival (EFS), and relapse-free survival (RFS) at 3 years were 69%, 55%, and 62%, respectively. The 12-month RFS and OS after transplant were 71% and 87%, respectively. Landmark analysis at 175 days from the time of CR/CRi (longest time to HCT), showed statistically superior advantages for RFS and OS (p=0.038 and 0.037, respectively) for the transplanted patients. Addition of dasatinib to chemotherapy and HCT for younger patients with Ph+ ALL is feasible and warrants further testing.
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http://dx.doi.org/10.1182/bloodadvances.2016001495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915PMC
December 2016

Total Marrow Lymphoid Irradiation/Fludarabine/ Melphalan Conditioning for Allogeneic Hematopoietic Cell Transplantation.

Biol Blood Marrow Transplant 2018 02 12;24(2):301-307. Epub 2017 Oct 12.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California; Department of Pediatrics, City of Hope National Medical Center, Duarte, California.

Reduced-intensity conditioning (RIC) regimens for hematopoietic stem cell transplantation (HCT) can reduce morbidity and mortality, but patients with advanced disease may require alternative approaches. In an initial report of RIC with fludarabine (FLU) and melphalan (MEL) with total marrow lymphoid irradiation (TMLI) in HCT for advanced hematologic malignancies in 33 patients, we found that the addition of TMLI to RIC was feasible and safe. Here we report long-term outcomes for these patients. This prospective study included 61 patients treated with TMLI to a dose of 12 Gy (1.5 Gy twice daily for 4 days), FLU (25 mg/m/day for 5 days), and MEL (140 mg/m/day for 1 day). Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) were measured from the date of HCT. Survival outcomes were analyzed using Kaplan-Meier analysis. Patients were categorized as low/intermediate or high/very high risk using the Disease Risk Index. The median follow-up was 7.4 years. The majority of patients had acute leukemia (72%); 49% had high/very high-risk disease. The median patient age was 55 years (range, 9-70 years). Two-year OS, EFS, CIR, and NRM were 54% (95% confidence interval [CI], 41%-66%), 49% (95% CI, 36%-61%), 21% (95% CI, 13%-35%), and 30% (95% CI, 20%-43%), respectively. Five-year OS, EFS, CIR, and NRM were 42% (95% CI, 30%-54%), 41% (95% CI, 28%-53%), 26 (95% CI, 17%-40%), and 33% (95% CI, 23%-47%, respectively). Acute (any grade) and chronic (limited or extensive) graft-versus-host disease occurred in 69% and 74% of patients, respectively. The most common toxicity was mucositis. The addition of TMLI to FLU/MEL conditioning was well tolerated, with favorable outcomes. Dosage escalation of TMLI or other modifications may be needed to improve disease control.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.019DOI Listing
February 2018

Synthesis, Positron Emission Tomography Imaging, and Therapy of Diabody Targeted Drug Lipid Nanoparticles in a Prostate Cancer Murine Model.

Cancer Biother Radiopharm 2017 Sep;32(7):247-257

2 Department of Molecular Immunology, Beckman Research Institute , City of Hope, Duarte, California.

The blood clearance of chemotherapeutic drugs such as doxorubicin (Dox) can be extended by incorporation into lipid nanoparticles (LNPs) and further improved by tumor targeting with antibody fragments. We used positron emission tomography (PET) imaging in a murine prostate cancer model to evaluate tumor targeting of LNPs incorporating Dox and antiprostate-specific membrane antigen (PSMA) diabodies. Dox-LNPs were generated by mixing or covalent attachment to water soluble distearoylphosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG). Cu-64 PET imaging was performed with DOTA-conjugated Dox, PEG-LNP, or an anti-PSMA site-specific cysteine-diabody. Since the mixture Dox+PEG-LNP was unstable in serum, further studies utilized Dox covalently bound to LNP ± covalently bound DOTA-cys-diabody (cys-DB)-LNP. Blood clearance of covalent Dox-PEG-LNP was slower than Dox alone or Dox+PEG-LNP. PET imaging of Cu-DOTA-Dox-PEG-LNP reached a maximum of 10% ID/g in tumors compared with 3% ID/g of Cu-DOTA-Dox, due to the prolonged blood clearance. Mixing Cu-DOTA-cys-DB-PEG-LNP with covalent Dox-PEG-LNP gave LNPs containing both drug and tumor targeting cys-DB. The mixed LNPs exhibited increased tumor uptake (15% ID/g) versus untargeted Cu-DOTA-Dox-PEG-LNPs (10% ID/g) demonstrating feasibility of the approach. Based on these results, a therapy study with mixed LNPs containing cys-DB-LNP and either Dox-LNP or the antitubulin drug auristatin-LNP showed significant reduction of tumor growth with the auristatin-diabody-LNP mixture, but not the Dox-diabody-LNP mixture.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646751PMC
http://dx.doi.org/10.1089/cbr.2017.2253DOI Listing
September 2017

Phase I/II Trial of Anticarcinoembryonic Antigen Radioimmunotherapy, Gemcitabine, and Hepatic Arterial Infusion of Fluorodeoxyuridine Postresection of Liver Metastasis for Colorectal Carcinoma.

Cancer Biother Radiopharm 2017 Sep;32(7):258-265

Department of Radiation Oncology, City of Hope National Medical Center , Duarte, California.

Objectives: Report the feasibility, toxicities, and long-term results of a Phase I/II trial of Y-labeled anticarcinoembryonic antigen (anti-CEA) (cT84.66) radioimmunotherapy (RIT), gemcitabine, and hepatic arterial infusion (HAI) of fluorodeoxyuridine (FUdR) after maximal hepatic resection of metastatic colorectal cancer to the liver.

Methods: Patients with metastatic colorectal cancer to the liver postresection or ablation to minimum disease were eligible. Each cohort received HAI of FUdR for 14 days on a dose escalation schedule. The maximum HAI FUdR dose level planned was 0.2 mg/kg/day, which is the standard dose for HAI FUdR alone. On day 9, Y-cT84.66 anti-CEA at 16.6 mCi/m as an i.v. bolus infusion and on days 9-11 i.v. gemcitabine at 105 mg/m were given. Patients could receive up to three cycles every 6 weeks of protocol therapy. Four additional cycles of HAI FUdR were allowed after RIT.

Results: Sixteen patients were treated on this study. A maximum tolerated dose of 0.20 mg/kg/day of HAI FUdR combined with RIT at 16.6 mCi/m and gemcitabine at 105 mg/m was achieved with only 1 patient experiencing grade 3 reversible toxicity (mucositis). After surgery, 10 patients had no evidence of visible disease and remained without evidence of disease after completion of protocol therapy. The remaining 6 patients demonstrated radiological visible disease after surgery and after protocol therapy 2 patients had a CR, 1 patient had PR, 2 had stable disease, and 1 had progression. With a median follow-up of 41.8 months (18.7-114.6), median progression free survival was 9.6 months. Two patients demonstrated long-term disease control out to 45+ and 113+ months.

Conclusion: This study demonstrates the safety, feasibility, and potential utility of HAI FUdR, RIT, and systemic gemcitabine. The trimodality approach does not have higher hematologic toxicities than seen in prior RIT-alone studies. Future efforts evaluating RIT in colorectal cancer should integrate RIT with systemic and regional therapies in the minimal tumor burden setting.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5646801PMC
http://dx.doi.org/10.1089/cbr.2017.2223DOI Listing
September 2017

Characterization of 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[Methoxy(polyethylene glycerol)-2000] and Its Complex with Doxorubicin Using Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics.

Bioconjug Chem 2017 06 9;28(6):1777-1790. Epub 2017 Jun 9.

Department of Radiation Oncology, City of Hope National Medical Center , Duarte, California 91010, United States.

Polyethylene glycol (PEG) lipid nanoparticles (LNPs) spontaneously assemble in water, forming uniformly sized nanoparticles incorporating drugs with prolonged blood clearance compared to drugs alone. Previously, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycerol)-2000] (DSPE-PEG) and several drug adducts, including doxorubicin, were analyzed by a combination of physical and molecular dynamic (MD) studies. In this study, a complete chemical shift assignment of DSPE-PEG plus or minus doxorubicin was achieved using nuclear magnetic resonance (NMR), one-dimensional selective nuclear Overhauser spectroscopy (1D-selNOESY), NOESY, correlation spectroscopy (COSY), total correlated spectroscopy (TOCSY), heteronuclear single quantum coherence (HSQC), and HSQC-TOCSY. Chemical shift perturbation, titration, relaxation enhancement, and NOESY analysis combined with MD reveal detailed structural information at the atomic level, including the location of doxorubicin in the micelle, its binding constant, the hydrophilic shell organization, and the mobility of the PEG tail, demonstrating that NMR spectroscopy can characterize drug-DSPE-PEG micelles with molecular weights above 180 kDa. The MD study revealed that an initial spherical organization led to a more-disorganized oblate structure in an aqueous environment and agreed with the NMR study in the details of the fine structure, in which methyl group(s) of the stearic acid in the hydrophobic core of the micelle are in contact with the phosphate headgroup of the lipid. Although the molecular size of the LNP drug complex is about 180 kDa, atomic resolution can be achieved by NMR-based methods that reveal distinct features of the drug-lipid interactions. Because many drugs have unfavorable blood clearance that may benefit from incorporation into LNPs, a thorough knowledge of their physical and chemical properties is essential to moving them into a clinical setting. This study provides an advanced basic approach that can be used to study a wide range of drug-LNP interactions.
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http://dx.doi.org/10.1021/acs.bioconjchem.7b00238DOI Listing
June 2017

Variations of target volume definition and daily target volume localization in stereotactic body radiotherapy for early-stage non-small cell lung cancer patients under abdominal compression.

Med Dosim 2017 Summer;42(2):116-121. Epub 2017 Apr 19.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA 91010.

We aimed to compare gross tumor volumes (GTV) in 3-dimensional computed tomography (3DCT) simulation and daily cone beam CT (CBCT) with the internal target volume (ITV) in 4-dimensional CT (4DCT) simulation in stereotactic body radiotherapy (SBRT) treatment of patients with early-stage non-small cell lung cancer (NSCLC) under abdominal compression. We retrospectively selected 10 patients with NSCLC who received image-guided SBRT treatments under abdominal compression with daily CBCT imaging. GTVs were contoured as visible gross tumor on the planning 3DCT and daily CBCT, and ITVs were contoured using maximum intensity projection (MIP) images of the planning 4DCT. Daily CBCTs were registered with 3DCT and MIP images by matching of bony landmarks in the thoracic region to evaluate interfractional GTV position variations. Relative to MIP-based ITVs, the average 3DCT-based GTV volume was 66.3 ± 17.1% (range: 37.5% to 92.0%) (p < 0.01 in paired t-test), and the average CBCT-based GTV volume was 90.0 ± 6.7% (daily range: 75.7% to 107.1%) (p = 0.02). Based on bony anatomy matching, the center-of-mass coordinates for CBCT-based GTVs had maximum absolute shift of 2.4 mm (left-right), 7.0 mm (anterior-posterior [AP]), and 5.2 mm (superior-inferior [SI]) relative to the MIP-based ITV. CBCT-based GTVs had average overlapping ratio of 81.3 ± 11.2% (range: 45.1% to 98.9%) with the MIP-based ITV, and 57.7 ± 13.7% (range: 35.1% to 83.2%) with the 3DCT-based GTV. Even with abdominal compression, both 3DCT simulations and daily CBCT scans significantly underestimated the full range of tumor motion. In daily image-guided patient setup corrections, automatic bony anatomy-based image registration could lead to target misalignment. Soft tissue-based image registration should be performed for accurate treatment delivery.
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http://dx.doi.org/10.1016/j.meddos.2017.01.008DOI Listing
March 2018

PET imaging of Cu-DOTA-scFv-anti-PSMA lipid nanoparticles (LNPs): Enhanced tumor targeting over anti-PSMA scFv or untargeted LNPs.

Nucl Med Biol 2017 Apr 17;47:62-68. Epub 2017 Jan 17.

Department of Molecular Immunology, Beckman Research Institute, City of Hope, Duarte, CA, 91010-3000, USA. Electronic address:

Introduction: Single chain (scFv) antibodies are ideal targeting ligands due to their modular structure, high antigen specificity and affinity. These monovalent ligands display rapid tumor targeting but have limitations due to their fast urinary clearance.

Methods: An anti-prostate membrane antigen (PSMA) scFv with a site-specific cysteine was expressed and evaluated in a prostate cancer xenograft model by Cu-64 PET imaging. To enhance tumor accumulation, the scFv-cys was conjugated to the co-polymer DSPE-PEG-maleimide that spontaneously assembled into a homogeneous multivalent lipid nanoparticle (LNP).

Results: The targeted LNP exhibited a 2-fold increase in tumor uptake compared to the scFv alone using two different thiol ester chemistries. The anti-PSMA scFv-LNP exhibited a 1.6 fold increase in tumor targeting over the untargeted LNP.

Conclusions: The targeted anti-PSMA scFv-LNP showed enhanced tumor accumulation over the scFv alone or the untargeted DOTA-micelle providing evidence for the development of this system for drug delivery.

Advances In Knowledge And Implications For Patient Care: Anti-tumor scFv antibody fragments have not achieved their therapeutic potential due to their fast blood clearance. Conjugation to an LNP enables multivalency to the tumor antigen as well as increased molecular size for chemotherapy drug delivery.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348925PMC
April 2017

Estimation of radiation-induced secondary cancer risks for early-stage non-small cell lung cancer patients after stereotactic body radiation therapy.

Pract Radiat Oncol 2017 May - Jun;7(3):e185-e194. Epub 2016 Oct 19.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California.

Purpose: In this study, we evaluated radiation-induced secondary lung cancer risks for the lung and the breast from stereotactic body radiation therapy treatment of early-stage non-small cell lung cancer with different radiation therapy treatment modalities.

Methods And Materials: Ten patients (5 men and 5 women) with early-stage non-small cell lung cancer who received definitive stereotactic body radiation therapy treatments were retrospectively selected. For each patient, two 3-dimensional conformal radiation therapy (3D-CRT) plans using 6- and 10-MV photons, respectively; a helical tomotherapy (HT) plan; and 2 volumetric modulated arc therapy (VMAT) plans using 1 and 2 arcs, respectively, were generated. The excess absolute risk (EAR) for secondary cancer occurrence was calculated using 3 organ equivalent dose models: the linear-exponential model, the plateau model, and the linear model for prescription dose range of 30 to 70 Gy.

Results: The 3D-CRT plans showed significantly lower monitor units compared with the rotational intensity modulate radiation therapy plans. Based on each of the 3 organ equivalent dose models, HT and VMAT plans showed comparable average EARs to both the lung and the breast compared with the 3D-CRT plans in the prescription dose range of 30 to 70 Gy. At a prescription dose of 50 Gy and using the linear-exponential model, the average lung EAR estimation ranged from 15.7 ± 5.3 to 16.0 ± 6.5 per 10,000 patients per year with the 5 delivery techniques, and the average EAR estimation for the breast ranged from 18.0 ± 14.0 to 21.0 ± 15.0 per 10,000 patients per year. The secondary cancer risk increased approximately linearly with mean organ dose. The 3D-CRT plans showed significantly higher secondary cancer risk for the ipsilateral lung and lower risk for the contralateral lung compared with the HT and VMAT plans.

Conclusions: Rotational intensity modulate radiation therapy techniques including helical tomotherapy and VMAT do not increase secondary cancer risks for the lung or the breast compared with 3D-CRT techniques, despite higher monitor units used.
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http://dx.doi.org/10.1016/j.prro.2016.10.009DOI Listing
February 2018

Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.

Acta Oncol 2016 Dec 20;55(12):1392-1399. Epub 2016 Oct 20.

a Department of Radiation Oncology , City of Hope National Medical Center , Duarte , CA , USA.

Background: Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision.

Material And Methods: A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000-2013 from the National Oncology Data Alliance™ (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR.

Results: On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT.

Conclusion: Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery.
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http://dx.doi.org/10.1080/0284186X.2016.1235797DOI Listing
December 2016

Focal therapy using magnetic resonance image-guided focused ultrasound in patients with localized prostate cancer.

J Ther Ultrasound 2016 11;4. Epub 2016 Mar 11.

Department of Radiation Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010 USA.

Background: The purpose of this study is to evaluate and report the feasibility, safety, and initial outcomes of patients with limited localized prostate cancer treated using a trans-rectal magnetic resonance image-guided focused ultrasound (MRGFUS) device. Attempts to focally treat only the index lesion for prostate cancer have been explored to reduce side effects while maintaining oncologic control. MRGFUS allows for precise targeting of thermal ablative therapy with real-time thermometry.

Methods: Three patients underwent multiparametric 3T MRI and TRUS-guided 16-sector mapping biopsies of the prostate. The patients were eligible if they had Gleason 6 or 7 (3 + 4) disease, no MRI-visible tumor ≥15 mm, no extracapsular extension, and no more than two discrete cancerous lesions ≤10 mm in length. Acoustic power was adjusted to achieve temperatures of 65 to 85 °C.

Results: Age ranged from 60 to 64 years. The number of biopsy-positive sectors treated ranged from 2 to 4. Post therapy, 16-sector biopsies at 6 months were negative in two patients with one patient still with Gleason 6 cancer (10 %, 2 mm) in one core. 16-sector biopsy in the first patient remains negative at 24 months. PSA continues to remain stable in all patients. IPSS in all patients either remained stable or decreased then stabilized. Erectile function according to the International Index of Erectile Function (IIEF) was excellent for all patients and demonstrated no decline up to the time of last follow-up at 12-24 months.

Conclusions: MRGFUS is a feasible alternative for focal therapy in a select subset of patients with prostate cancer. The treatment is well tolerated with no evidence of decline in functional outcomes. Initial post-therapy biopsy results are promising. Long-term treatment efficacy requires further study.
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http://dx.doi.org/10.1186/s40349-016-0054-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788859PMC
March 2016

Stage I and II Endometrial Adenocarcinoma: Analysis of 2009 FIGO Staging Revision and Impact on Survival by Adjuvant Therapy.

Am J Clin Oncol 2018 03;41(3):302-306

Department of Radiation Oncology, City of Hope National Medical Center, City of Hope, Duarte, CA.

Background: In 2009, the International Federation of Gynecology and Obstetrics revised the staging classification for endometrial cancer. Mucosal cervical involvement was eliminated from the criteria and only those with stromal cervical involvement were considered stage II. We examined the implications of the staging changes and the survival impact of adjuvant therapy in stage I to II endometrial adenocarcinoma.

Materials And Methods: Data were obtained from the National Oncology Data Alliance. Stage I to II endometrial adenocarcinoma patients diagnosed between 1988 and 2008 were identified and grouped according to the 1988 International Federation of Gynecology and Obstetrics staging. Multivariate analysis (MVA) was performed using proportional hazards model; comparison of Kaplan-Meier survival curves was based on the log-rank statistic.

Results: A total of 14,158 patients with stage I to II endometrial adenocarcinoma were identified with a median follow-up of 41 months. Adjuvant external-beam radiation therapy (EBRT) and adjuvant vaginal brachytherapy (VB) were positive predictors for overall survival (OS) only in IC, IIA, and IIB. On MVA, stages IA and IB OS did not differ (P=0.17), IIA had worse OS compared with IC (P<0.05), and IIA OS did not differ from IIB (P=0.57). Neither IA nor IB benefited from adjuvant radiotherapy on MVA. However, both IC and IIA had OS improvements with VB±EBRT (P<0.05) with the greatest impact from the VB.

Conclusions: Mucosal cervical involvement represents a risk factor and should be considered when determining adjuvant therapy. Adjuvant therapy provided no survival benefit in 1988 stage IA or IB; however, adjuvant radiotherapy is recommended in the management of IC, IIA, and IIB.
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http://dx.doi.org/10.1097/COC.0000000000000273DOI Listing
March 2018

Combined Effects of Suberoylanilide Hydroxamic Acid and Cisplatin on Radiation Sensitivity and Cancer Cell Invasion in Non-Small Cell Lung Cancer.

Mol Cancer Ther 2016 05 2;15(5):842-53. Epub 2016 Feb 2.

Department of Oncology, Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, China. Affiliated Hangzhou First People's Hospital of Zhejiang Chinese Medical University, Hangzhou, China.

Lung cancer is a leading cause of cancer-related mortality worldwide, and concurrent chemoradiotherapy has been explored as a therapeutic option. However, the chemotherapeutic agents cannot be administered for most patients at full doses safely with radical doses of thoracic radiation, and further optimizations of the chemotherapy regimen to be given with radiation are needed. In this study, we examined the effects of suberoylanilide hydroxamic acid (SAHA) and cisplatin on DNA damage repairs, and determined the combination effects of SAHA and cisplatin on human non-small cell lung cancer (NSCLC) cells in response to treatment of ionizing radiation (IR), and on tumor growth of lung cancer H460 xenografts receiving radiotherapy. We also investigated the potential differentiation effect of SAHA and its consequences on cancer cell invasion. Our results showed that SAHA and cisplatin compromise distinct DNA damage repair pathways, and treatment with SAHA enhanced synergistic radiosensitization effects of cisplatin in established NSCLC cell lines in a p53-independent manner, and decreased the DNA damage repair capability in cisplatin-treated primary NSCLC tumor tissues in response to IR. SAHA combined with cisplatin also significantly increased inhibitory effect of radiotherapy on tumor growth in the mouse xenograft model. In addition, SAHA can induce differentiation in stem cell-like cancer cell population, reduce tumorigenicity, and decrease invasiveness of human lung cancer cells. In conclusion, our data suggest a potential clinical impact for SAHA as a radiosensitizer and as a part of a chemoradiotherapy regimen for NSCLC. Mol Cancer Ther; 15(5); 842-53. ©2016 AACR.
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http://dx.doi.org/10.1158/1535-7163.MCT-15-0445DOI Listing
May 2016

The impact of increasing dose on overall survival in prostate cancer.

Radiat Oncol 2015 May 21;10:115. Epub 2015 May 21.

Department of Radiation Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA, 91010, USA.

Purpose: To assess the impact of increasing dose on overall survival (OS) for prostate cancer patients.

Methods: Treatment data were obtained on more than 20,000 patients in the National Oncology Data Alliance®, a proprietary database of merged tumor registries, who were treated for prostate cancer with definitive radiotherapy between 1995 and 2006. Eligible patients had complete data on total dose, T stage, use and timing of androgen deprivation therapy (ADT), and treatment start date (n = 20,028). Patients with prior malignancies were excluded.

Results: On multivariate analysis, dose, T stage, grade, marital status, age, and neoadjuvant ADT were significant predictors of OS. Hazard ratios for OS declined monotonically with increasing dose, reaching 0.63 (95 % Confidence Interval 0.53-0.76) at ≥80 Gy. On subset analysis, neoadjuvant ADT significantly improved OS in high risk patients but was not significant in lower risk patients. The dose response was maintained across all risk groups. Medical comorbidities were balanced across all dose strata and sensitivity analysis demonstrated that other prognostic factors were unlikely to explain the observed dose response.

Conclusions: This study suggests that increasing dose significantly improves OS in prostate cancer patients treated with radiotherapy.
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http://dx.doi.org/10.1186/s13014-015-0419-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448310PMC
May 2015
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