MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre study.

BACKGROUND: Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer. METHODS: In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting. FINDINGS: Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths. INTERPRETATION: 24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term. FUNDING: Insightec and the National Cancer Institute.

Comparison of intrafractional motion with two frameless immobilization systems in surface-guided intracranial stereotactic radiosurgery.

PURPOSE/OBJECTIVES: The aim of this study is to compare intrafractional motion using two commercial non-invasive immobilization systems for linac-based intracranial stereotactic radiosurgery (SRS) under guidance with a surface-guided radiotherapy (SGRT) system. MATERIALS/METHODS: Twenty-one patients who received intracranial SRS were retrospectively selected. Ten patients were immobilized with a vacuum fixation biteplate system, while 11 patients were immobilized with an open-face mask system. A setup margin of 1 mm was used in treatment planning. Real-time surface motion data in 37 treatment fractions using the vacuum fixation system and 44 fractions using the open-face mask were recorded by an SGRT system. Variances of intrafractional motion along three translational directions and three rotational directions were compared between the two immobilization techniques with Levene's tests. Intrafractional motion variation over time during treatments was also evaluated. RESULTS: Using the vacuum fixation system, the average and standard deviations of the shifts were 0.01 ± 0.18 mm, -0.06 ± 0.30 mm, and  0.02 ± 0.26 mm in the anterior-posterior (AP), superior-inferior (SI), and left-right (LR) directions, and -0.02 ± 0.19°, -0.01 ± 0.13°, and 0.01 ± 0.13° for rotations in yaw, roll, and pitch, respectively; using the open-face mask system, the average and standard deviations of the shifts were -0.06 ± 0.20 mm, -0.02 ± 0.35 mm, and 0.01 ± 0.40 mm in the AP, SI, and LR directions, and were 0.05 ± 0.23°, 0.02 ± 0.21°, and 0.00 ± 0.16° for rotations in yaw, roll, and pitch, respectively. There was a significant increase in intrafractional motion variance over time during treatments. CONCLUSION: Patients with the vacuum fixation system had significantly smaller intrafractional motion variation compared to those with the open-face mask system. Using intrafractional motion techniques such as surface imaging system is recommended to minimize dose deviation due to intrafractional motion. The increase in intrafractional motion over time indicates clinical benefits with shorter treatment time.

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

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.

Antibody Targeted PET Imaging of 64Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA Positive Tumors.

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 64Cu. 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 64Cu-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.

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

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.

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

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/m2/day for 5 days), and MEL (140 mg/m2/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.

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.

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-PEG2000) 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-PEG2000 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 PEG2000 tail, demonstrating that NMR spectroscopy can characterize drug-DSPE-PEG2000 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.

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

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.

Impact of Total Lymph Node Count on Staging and Survival After Neoadjuvant Chemoradiation Therapy for Rectal Cancer.

PURPOSE: Current guidelines recommend that a minimum of 12 lymph nodes (LNs) be dissected to accurately stage rectal cancer patients. Neoadjuvant chemoradiation therapy (CRT) decreases the number of LNs retrieved at surgery. The purpose of this study was to assess the impact of the number of LNs dissected on overall survival (OS) for localized rectal cancer patients treated with neoadjuvant CRT. METHODS: Treatment data were obtained on all patients treated for rectal cancer (2000-2013) in the National Oncology Data Alliance™, a proprietary database of merged tumor registries. Eligible patients were treated with neoadjuvant CRT followed by surgery and had complete data on number of positive LNs, number of LNs examined, and treatment dates (n = 4565). RESULTS: Hazard ratios for OS decreased sequentially with increasing number of LNs examined until a maximum benefit was achieved with examination of eight LNs. On multivariate analysis, age, sex, race, marital status, grade, ypT stage, ypN stage, type of surgery, margin status, presence of pathologically confirmed metastasis at surgery, and number of LNs examined were significant predictors of OS. CONCLUSIONS: Examination of eight or more LNs in rectal cancer patients treated with neoadjuvant CRT resulted in accurate staging and assignment into prognostic groups with an ensuing improvement in OS by stage. This study suggests that eight LNs is the threshold for an adequate lymph node dissection after neoadjuvant CRT.

First-In-Human Pilot PET Immunoimaging Study of 64Cu-Anti-Carcinoembryonic Antigen Monoclonal Antibody (hT84.66-M5A) in Patients with Carcinoembryonic Antigen-Producing Cancers.

Background: PET imaging using radiolabeled immunoconstructs shows promise in cancer detection and in assessing tumor response to therapies. The authors report the first-in-human pilot study evaluating M5A, a humanized anti-carcinoembryonic antigen (CEA) monoclonal antibody (mAb), radiolabeled with 64Cu in patients with CEA-expressing malignancies. The purpose of this pilot study was to identify the preferred patient population for further evaluation of this agent in an expanded trial. Methods: Patients with CEA-expressing primary or metastatic cancer received 64Cu-DOTA-hT84.66-M5A with imaging performed at 1 and 2 days postinfusion. 64Cu-DOTA-hT84.66-M5A PET scan findings were correlated with CT, MRI, and/or FDG PET scans and with histopathologic findings from planned surgery or biopsy performed postscan. Results: Twenty patients received 64Cu-DOTA-hT84.66-M5A. Twelve patients demonstrated positive images, which were confirmed in 10 patients as tumor by standard-of-care (SOC) imaging, biopsy, or surgical findings. Four of the 8 patients with negative imaging were confirmed as true negative, with the remaining 4 patients having disease demonstrated by SOC imaging or surgery. All 5 patients with locally advanced rectal cancer underwent planned biopsy or surgery after 64Cu-DOTA-hT84.66-M5A imaging (4 patients imaged 6-8 weeks after completing neoadjuvant chemotherapy and radiation therapy) and demonstrated a high concordance between biopsy findings and 64Cu-DOTA-hT84.66-M5A PET scan results. Three patients demonstrated positive uptake at the primary site later confirmed by biopsy and at surgery as residual disease. Two patients with negative scans each demonstrated complete pathologic response. In 5 patients with medullary thyroid cancer, 64Cu-DOTA-hT84.66-M5A identified disease not seen on initial CT scans in 3 patients, later confirmed to be disease by subsequent surgery or MRI. Conclusions: 64Cu-DOTA-hT84.66-M5A demonstrates promise in tumor detection, particularly in patients with locally advanced rectal cancer and medullary thyroid cancer. A successor trial in locally advanced rectal cancer has been initiated to further evaluate this agent's ability to define tumor extent before and assess disease response after neoadjuvant chemotherapy and radiotherapy. clinical trial.gov (NCT02293954).

Considerations for intensity modulated total body or total marrow and lymphoid irradiation.

We compiled a sampling of the treatment techniques of intensity-modulated total body irradiation, total marrow irradiation and total marrow and lymphoid irradiation utilized by several centers across North America and Europe. This manuscript does not serve as a consensus guideline, but rather is meant to serve as a convenient reference for centers that are considering starting an intensity-modulated program.

Target Coverage and Normal Organ Sparing in Dose-Escalated Total Marrow and Lymphatic Irradiation: A Single-Institution Experience.

Purpose/Objectives: The aim of this study is to report historical treatment planning experience at our institution for patients receiving total marrow and lymphatic irradiation (TMLI) as part of the conditioning regimen prior to hematopoietic stem cell transplant. Materials/Methods: Based on a review of all historical clinical TMLI treatments plans, we retrieved a 12-Gy cohort of 108 patients with a prescription dose of 12 Gy to the skeletal bones, lymph nodes, spleen, and spinal canal, and retrieved a 20-Gy cohort of 120 patients with an escalated prescription dose of 20 Gy to the skeletal bones, lymph nodes, spleen, and spinal cord, and 12 Gy to the brain and liver. Representative dosimetric parameters including mean and median dose, D80, and D10 (dose covering 80% and 10% of the structure volume, respectively) for targets and normal organs were extracted and compared between the two groups of patients. Results: For the 12-Gy cohort, the average mean dose for normal organs ranged from 18.3% to 78.3% of 12 Gy, and the average median dose ranged from 18.3% to 77.5% of 12 Gy. For the 20-Gy cohort, the average mean dose for normal organs ranged from 13.0% to 76.0% of 20 Gy, and the average median dose ranged from 12.5% to 75.0% of 20 Gy. Compared to the mean dose to normal organs in the 12-Gy cohort, the average mean dose to normal organs increased from 0.0% to 73.1%, with only four normal organs showing a >50% increase. Normal organ dose in TMLI plans using volumetric modulated arc therapy fields fell within the dose range in historical TMLI plans. Conclusion: Dosimetric data in historical TMLI plans at our institution are summarized at prescription dose levels of 12 Gy and 20 Gy, respectively. Compared to the normal organ dose with a prescription dose of 12 Gy, the mean and median dose to most normal organs at an escalated prescription dose of 20 Gy had an increase less than prescription dose scaling. Dosimetric results from this study can be used as reference data to facilitate clinical implementation of TMLI at other institutions.

Volumetric modulated arc therapy based total marrow and lymphoid irradiation: Workflow and clinical experience.

Background: The aim of this study is to report historical treatment planning experience at our institution for patients receiving total marrow and lymphatic irradiation (TMLI) using volumetric modulated arc therapy (VMAT) as part of the conditioning regimen prior to hematopoietic stem cell transplant. Methods: We identified a total of fifteen patients with VMAT TMLI, ten with a prescription dose of 20 Gy (targeting the skeletal bones, lymph nodes, spleen, and spinal canal, with 12 Gy to the brain and liver) and five with a prescription dose of 12-16 Gy (targeting the skeletal bones, lymph nodes, spleen, and spinal canal). Representative dosimetric parameters including total treatment time, mean and median dose, D80, and D10 (dose covering 80% and 10% of the structure volume, respectively) for targets and normal organs were extracted and compared to historical patients treated with helical tomotherapy. Results: The median treatment time for the first and subsequent fractions was 1.5 and 1.1 hours, respectively. All the target volumes had a mean dose greater than the prescribed dose except the ribs, which had an average mean dose of 19.5 Gy. The skeletal bones had an average mean dose of 21.1 Gy. The brain and liver have average mean doses of 14.8 and 14.1 Gy, respectively. The mean lung dose had an average of 7.6 ± 0.6 Gy for the 20-Gy cohort. Relative to the prescription dose of 20 Gy, the average mean dose for the normal organ volumes ranged from 16.5% to 72.0%, and the average median dose for the normal organs ranged from 16.5% to 71.0%. Dosimetry for patients treated to 12-16 Gy fell within expected ranges based on historical helical tomotherapy plans. Conclusions: Dosimetric data in the VMAT TMLI plans at our institution are summarized for 20 Gy and 12-16 Gy cohorts. Dose distributions and treatment times are overall similar to plans generated with helical tomotherapy. TMLI may be delivered effectively using a VMAT technique, even at escalated doses.

Total marrow irradiation (TMI): Addressing an unmet need in hematopoietic cell transplantation - a single institution experience review.

Purpose: TMI utilizes IMRT to deliver organ sparing targeted radiotherapy in patients undergoing hematopoietic cell transplantation (HCT). TMI addresses an unmet need, specifically patients with refractory or relapsed (R/R) hematologic malignancies who have poor outcomes with standard HCT regimens and where attempts to improve outcomes by adding or dose escalating TBI are not possible due to increased toxicities. Over 500 patients have received TMI at this center. This review summarizes this experience including planning and delivery, clinical results, and future directions. Methods: Patients were treated on prospective allogeneic HCT trials using helical tomographic or VMAT IMRT delivery. Target structures included the bone/marrow only (TMI), or the addition of lymph nodes, and spleen (total marrow and lymphoid irradiation, TMLI). Total dose ranged from 12 to 20 Gy at 1.5-2.0 Gy fractions twice daily. Results: Trials demonstrate engraftment in all patients and a low incidence of radiation related toxicities and extramedullary relapses. In R/R acute leukemia TMLI 20 Gy, etoposide, and cyclophosphamide (Cy) results in a 1-year non-relapse mortality (NRM) rate of 6% and 2-year overall survival (OS) of 48%; TMLI 12 Gy added to fludarabine (flu) and melphalan (mel) in older patients (≥ 60 years old) results in a NRM rate of 33% comparable to flu/mel alone, and 5-year OS of 42%; and TMLI 20 Gy/flu/Cy and post-transplant Cy (PTCy) in haplo-identical HCT results in a 2-year NRM rate of 13% and 1-year OS of 83%. In AML in complete remission, TMLI 20 Gy and PTCy results in 2-year NRM, OS, and GVHD free/relapse-free survival (GRFS) rates of 0%, 86·7%, and 59.3%, respectively. Conclusion: TMI/TMLI shows significant promise, low NRM rates, the ability to offer myeloablative radiation containing regimens to older patients, the ability to dose escalate, and response and survival rates that compare favorably to published results. Collaboration between radiation oncology and hematology is key to successful implementation. TMI/TMLI represents a paradigm shift from TBI towards novel strategies to integrate a safer and more effective target-specific radiation therapy into HCT conditioning beyond what is possible with TBI and will help expand and redefine the role of radiotherapy in HCT.

Feasibility of a Novel Sparse Orthogonal Collimator-Based Preclinical Total Marrow Irradiation for Enhanced Dosimetric Conformality.

Total marrow irradiation (TMI) has significantly improved radiation conditioning for hematopoietic cell transplantation in hematologic diseases by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. Recently, preclinical three-dimensional image-guided TMI has been developed to enhance mechanistic understanding of the role of TMI and to support the development of experimental therapeutics. However, a dosimetric comparison between preclinical and clinical TMI reveals that the preclinical TMI treatment lacks the ability to reduce the dose to some of the vital organs that are very close to the skeletal system and thus limits the ability to evaluate radiobiological relevance. To overcome this limit, we introduce a novel Sparse Orthogonal Collimator (SOC)-based TMI and evaluate its ability to enhance dosimetric conformality. The SOC-TMI-based dose modulation technique significantly improves TMI treatment planning by reducing radiation exposures to critical organs that are close to the skeletal system that leads to reducing the gap between clinical and preclinical TMI.

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide.

Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.

Role of radiotherapy in treatment of extramedullary relapse following total marrow and lymphoid irradiation in high-risk and/or relapsed/refractory acute leukemia.

Background: Total Marrow and Lymphoid Irradiation (TMLI) is a promising component of the preparative regimen for hematopoietic cell transplantation in patients with high-risk acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Extramedullary (EM) relapse after TMLI is comparable to TBI and non-TBI conditioning regimens. This study evaluates outcomes of patients treated with radiotherapy (RT) with EM relapse previously treated with TMLI. Methods: A retrospective analysis of five prospective TMLI trials was performed. TMLI targeted bones and major lymphoid tissues using image-guided tomotherapy, with total dose ranging from 12 to 20 Gy. EM recurrences were treated at the discretion of the hematologist and radiation oncologist using RT ± chemotherapy. Descriptive statistics and survival analysis were then performed on this cohort. Results: In total, 254 patients with refractory or relapsed AML or ALL were treated with TMLI at our institution. Twenty-one patients were identified as receiving at least one subsequent course of radiation. A total of 67 relapse sites (median=2 sites/patient, range=1-16) were treated. Eleven relapsed patients were initially treated with curative intent. Following the initial course of subsequent RT, 1-year, 3-year and 5-year estimates of OS were 47.6%, 32.7% and 16.3%, respectively. OS was significantly better in patients treated with curative intent, with median OS of 50.7 months vs 1.6 months (p<0.001). 1-year, 3-year and 5-year estimates of PFS were 23.8%, 14.3% and 14.3%, respectively. PFS was significantly better in patients treated with curative intent, with median PFS of 6.6 months vs 1.3 months (p<0.001). Following RT, 86.6% of the sites had durable local control. Conclusions: RT is an effective modality to treat EM relapse in patients with acute leukemia who relapse after HCT achieving high levels of local control. In patients with limited relapse amenable to curative intent, radiation confers favorable long-term survival. Radiation as salvage treatment for EM relapse after HCT warrants further evaluation.

A Mathematical Modeling Approach for Targeted Radionuclide and Chimeric Antigen Receptor T Cell Combination Therapy.

Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

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

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.