Embracing the Future of Clinical Trials in Radiotherapy: An NRG Oncology CIRO Technology Retreat Whitepaper on Pioneering Technologies and AI-Driven Solutions.

This white paper examines the potential of pioneering technologies and artificial intelligence (AI)-driven solutions in advancing clinical trials involving radiotherapy. As the field of radiotherapy evolves, the integration of cutting-edge approaches such as radiopharmaceutical dosimetry, FLASH radiotherapy, image-guided radiation therapy (IGRT), and AI promises to improve treatment planning, patient care, and outcomes. Additionally, recent advancements in quantum science, linear energy transfer/relative biological effect (LET/RBE), and the combination of radiotherapy and immunotherapy create new avenues for innovation in clinical trials.

MRI detects tubulointerstitial changes in mouse models of radiation-induced nephropathy.

Purpose: We hypothesized that radiation-induced tubulointerstitial changes in the kidney can be assessed using MRI-based T relaxation time measurements.

Methods: We performed MRI, histology, and serum biochemistry in two mouse models of radiation nephropathy: one involving external beam radiotherapy and the other using internal irradiation with an α-particle-emitting actinium-225 radiolabeled antibody. We compared the mean T values of different renal compartments between control and external beam radiotherapy or α-particle-emitting actinium-225 radiolabeled antibody-treated groups and between the two radiation-treated groups using a Wilcoxon rank-sum test.

Mathematic Modeling of Tumor Growth During [Lu]Lu-PSMA Therapy: Insights into Treatment Optimization.

The treatment regimen for [Lu]Lu-prostate-specific membrane antigen (PSMA) 617 therapy follows that of chemotherapy: 6 administrations of a fixed activity, each separated by 6 wk. Mathematic modeling can be used to test the hypothesis that the current treatment regimen for a radiopharmaceutical modality is suboptimal. A mathematic model was developed to describe tumor growth during [Lu]Lu-PSMA therapy.

Targeting erbB Pathways in Breast Cancer: Dual Kinase Inhibition for Brain Metastasis and Prevention of p185HER2/Neu Tumor Development.

Background: Breast cancer predominantly affects women and poses challenges in the treatment of both local and advanced diseases. In a previous study, we reported the effectiveness of ER121, a structurally resolved small compound specifically designed to target human cancers expressing or overexpressing mutant EGFR and HER2.

Purpose: The objective of this study is to assess the efficacy and toxicity of ER121 in metastatic and triple negative breast cancer (TNBC, HER2+) cells and tumor models.

Alpha and Beta Radiation for Theragnostics.

Targeted radionuclide therapy (TRT) has significantly evolved from its beginnings with iodine-131 to employing carrier molecules with beta emitting isotopes like lutetium-177. With the success of Lu-177-DOTATATE for neuroendocrine tumors and Lu-177-PSMA-617 for prostate cancer, several other beta emitting radioisotopes, such as Cu-67 and Tb-161, are being explored for TRT. The field has also expanded into targeted alpha therapy (TAT) with agents like radium-223 for bone metastases in prostate cancer, and several other alpha emitter radioisotopes with carrier molecules, such as Ac-225, and Pb-212 under clinical trials.

Therapeutic efficacy of an alpha-particle emitter labeled anti-GD2 humanized antibody against osteosarcoma-a proof of concept study.

Purpose: Current treatments for osteosarcoma (OS) have a poor prognosis, particularly for patients with metastasis and recurrence, underscoring an urgent need for new targeted therapies to improve survival. Targeted alpha-particle therapy selectively delivers cytotoxic payloads to tumors with radiolabeled molecules that recognize tumor-associated antigens. We have recently demonstrated the potential of an FDA approved, humanized anti-GD2 antibody, hu3F8, as a targeted delivery vector for radiopharmaceutical imaging of OS.

Gel-forming therapeutic peptide exhibits sustained delivery and efficacy in a mouse model of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a particularly aggressive and invasive subtype of breast cancer that represents a major cause of death of women worldwide. Here we describe the efficacy of an integrin-binding antiangiogenic peptide in a variety of delivery methods and dosing conditions. This peptide, AXT201, demonstrated consistent anti-tumor efficacy when administered intraperitoneally, subcutaneously, and intratumorally, and retained this activity even when dosing frequency was reduced to once every two weeks.

Girth-based administered activity for pediatric Tc-DMSA SPECT.

Background: Pediatric molecular imaging requires a balance between administering an activity that will yield sufficient diagnostic image quality while maintaining patient radiation exposure at acceptable levels. In current clinical practice, this balance is arrived at by the current North American Consensus Guidelines in which patient weight is used to recommend the administered activity (AA).

Purpose: We have previously demonstrated that girth (waist circumference at the level of the kidneys) is better at equalizing image quality than patient weight for pediatric Tc-99m DMSA renal function imaging.

Early Normal Tissue Effects and Bone Marrow Relative Biological Effectiveness for an Actinium 225-Labeled HER2/neu-Targeting Antibody.

Purpose: In this study we determined the dose-independent relative biological effectiveness (RBE2) of bone marrow for an anti-HER2/neu antibody labeled with the alpha-particle emitter actinium 225 (Ac). Hematologic toxicity is often a consequence of radiopharmaceutical therapy (RPT) administration, and dosimetric guidance to the bone marrow is required to limit toxicity.

Methods And Materials: Female neu/N transgenic mice (MMTV-neu) were intravenously injected with 0 to 16.

A persistent belief in radiopharmaceutical therapy.

Imaging and dosimetry physics are essential to the long-term success of radiopharmaceutical therapy (RPT), a cancer treatment modality that can deliver potent cytotoxic radiation to disseminated cancer cells. This is a review of my personal journey in this field.

May Help Manage Total and Volatile Acidity of Santorini-Assyrtiko Wine in View of Global Warming.

Non-Saccharomyces (NS) yeasts are gaining popularity in modern winemaking for improving wine quality. Climate change is one of the biggest challenges winegrowing now faces in warm regions. Here, Lachancea thermotolerans LtS1 and Torulaspora delbrueckii TdS6 combined with Saccharomyces cerevisiae ScS13 isolated from Assyrtiko grapes from Santorini island were evaluated in grape must fermentation with the aim to mitigate major consequences of temperature rise.

Improved accuracy of S-value-based dosimetry: a guide to transition from Cristy-Eckerman to ICRP adult phantoms.

Background: In 2016, the International Commission on Radiological Protection (ICRP) published the results of Monte Carlo simulations performed using updated and anatomically realistic voxelized phantoms. The resulting specific absorbed fractions are based on more realistic human anatomy than those computed in the stylized, geometrical Cristy-Eckerman (CE) phantom. Despite this development, the ICRP-absorbed fractions have not been widely adopted for radiopharmaceutical dosimetry.

Cure of Micrometastatic B-Cell Lymphoma in a SCID Mouse Model Using Bi-Anti-CD20 Monoclonal Antibody.

We studied the feasibility of using the α-emitting Bi-anti-CD20 therapy with direct bioluminescent tracking of micrometastatic human B-cell lymphoma in a SCID mouse model. A highly lethal SCID mouse model of minimal-tumor-burden disseminated non-Hodgkin lymphoma (NHL) was established using human Raji lymphoma cells transfected to express the luciferase reporter. In vitro and in vivo radioimmunotherapy experiments were conducted.

Bone Marrow Relative Biological Effectiveness for a Pb-labeled Anti-HER2/neu Antibody.

Purpose: We have determined the in vivo relative biological effectiveness (RBE) of an alpha-particle-emitting radiopharmaceutical therapeutic agent (Pb-labeled anti-HER2/neu antibody) for the bone marrow, a potentially dose-limiting normal tissue.

Methods And Materials: The RBE was measured in mice using femur marrow cellularity as the biological endpoint. External beam radiation therapy (EBRT), delivered by a small-animal radiation research platform was used as the reference radiation.

Anti-GD2 antibody for radiopharmaceutical imaging of osteosarcoma.

Purpose: Osteosarcoma (OS) is the most frequently diagnosed bone cancer in children with little improvement in overall survival in the past decades. The high surface expression of disialoganglioside GD2 on OS tumors and restricted expression in normal tissues makes it an ideal target for anti-OS radiopharmaceuticals. Since human and canine OS share many biological and molecular features, spontaneously occurring OS in canines has been an ideal model for testing new imaging and treatment modalities for human translation.

Methods of improving brain dose estimates for internally deposited radionuclides.

The US National Council on Radiation Protection and Measurements (NCRP) convened Scientific Committee 6-12 (SC 6-12) to examine methods for improving dose estimates for brain tissue for internally deposited radionuclides, with emphasis on alpha emitters. This Memorandum summarises the main findings of SC 6-12 described in the recently published NCRP Commentary No. 31, 'Development of Kinetic and Anatomical Models for Brain Dosimetry for Internally Deposited Radionuclides'.

I-124 PET/CT image-based dosimetry in patients with differentiated thyroid cancer treated with I-131: correlation of patient-specific lesional dosimetry to treatment response.

Purpose: The objective of this study is to evaluate the lesion absorbed dose (AD), biological effective dose (BED), and equivalent uniform dose (EUD) to clinical-response relationship in lesional dosimetry for I therapy.

Methods: Nineteen lesions in four patients with metastatic differentiated thyroid cancer (DTC) were evaluated. The patients underwent PET/CT imaging at 2 h, 24 h, 48 h, 72 h, and 96 h post administration of ~ 33-65 MBq (0.

Pb-conjugated anti-rat HER2/ antibody against a -N derived murine mammary carcinoma cell line: cell kill and RBE in vitro.

Purpose: In the current work, the RBE of a Pb-conjugated anti-HER2/ antibody construct has been evaluated, in vitro, by colony formation assay. The RBE was estimated by comparing two absorbed dose-survival curves: the first obtained from the conjugated Pb experiments (test radiation), the second obtained by parallel experiments of single bolus irradiation of external beam (reference radiation).

Materials And Methods: Mammary carcinoma NT2.

Dosimetry for Radiopharmaceutical Therapy: Current Practices and Commercial Resources.

With the ongoing dramatic growth of radiopharmaceutical therapy, research and development in internal radiation dosimetry continue to advance both at academic medical centers and in industry. The basic paradigm for patient-specific dosimetry includes administration of a pretreatment tracer activity of the therapeutic radiopharmaceutical; measurement of its time-dependent biodistribution; definition of the pertinent anatomy; integration of the measured time-activity data to derive source-region time-integrated activities; calculation of the tumor, organ-at-risk, and/or whole-body absorbed doses; and prescription of the therapeutic administered activity. This paper provides an overview of the state of the art of patient-specific dosimetry for radiopharmaceutical therapy, including current methods and commercially available software and other resources.

Tumor Response to Radiopharmaceutical Therapies: The Knowns and the Unknowns.

Radiopharmaceutical therapy (RPT) is defined as the delivery of radioactive atoms to tumor-associated targets. In RPT, imaging is built into the mode of treatment since the radionuclides used in RPT often emit photons or can be imaged using a surrogate. Such imaging may be used to estimate tumor-absorbed dose.

Combination of Carriers with Complementary Intratumoral Microdistributions of Delivered -Particles May Realize the Promise for Ac in Large, Solid Tumors.

α-particle radiotherapy has already been shown to be impervious to most resistance mechanisms. However, in established (i.e.