With the use of novel intervention methods, focused or more specifically targeted cancer radiation therapy can be delivered using particle or targeted radiation sources / radiopharmaceuticals. One example is the use of ⁹⁰Y-microspheres and intravascular delivery for the treatment of lesions in the liver. In this session, novel interventions with focused cancer radiation therapy will be presented, including the use of different radiation sources or radiopharmaceuticals, and novel delivery techniques for the focused radiation treatment of cancers in various locations.
1. Different kinds of radionuclides which may be used for focused cancer radiation therapy and their physics
2. Delivery techniques and applications for focused cancer radiation therapy
3. Current progress in focused cancer radiation therapy clinical trials
Therapy of glioblastoma using locoregional administration of ¹⁸⁶Re-liposomal nanoparticles
Ande Bao¹, William T. Phillips², John R. Floyd³, Toral R. Patel⁵, Jeffrey S. Weinberg⁶, Norman LaFrance⁷, Marc H. Hedrick⁷, Andrew J. Brenner⁴
¹. Department of Radiation Oncology, Seidman Cancer Center, University Hospitals Cleveland Medical Center, and School of Medicine, Case Western Reserve University, Cleveland, OH
². Departments of Radiology; ³. Neurosurgery; ⁴. Neuro-oncology, University of Texas Health Science Center San Antonio, San Antonio, TX
⁵. Department of Neurosurgery, University of Texas Southwestern Medical Center, Dallas, TX
⁶. Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX
⁷. Plus Therapeutics, Inc., Austin, TX
Purpose: Glioblastoma (GBM) has a high recurrence and low patient survival. GBM is a very radiation resistant tumor. Recurrent GBM, even with salvage radiation therapy, surgery, or chemotherapy, has an average survival of < 10 months. To overcome the dose limiting toxicities associated with the traditional radiation therapy, a clinical trial of focused radiation therapy for the treatment of GBM using ¹⁸⁶Re-nanoliposomes (186RNL) delivered by convection-enhanced intratumoral delivery (CED) has been conducted.
Method: This therapy technique is similar to brachytherapy in its procedure and therapy; but with the use of nanoparticle-carried ¹⁸⁶Re radionuclide. ¹⁸⁶Re is a β-emission radionuclide (347 KeV mean β-energy) with half life of 3.72 days, which also emits 10% of 137 KeV γ-ray for imaging distribution and therapy evaluation. The β-radiation has a range of 1.8 mm (90% energy deposition). The use of liposomal nanoparticles facilitates intratumoral radiation source dispersion mediated by convection force, followed by sustained locoregional retention for focused cancer radiation therapy and tumor eradication.
Results: The Phase 1 clinical trial on the treatment of recurrent GBM followed a dose escalation protocol from 37 to 1154.4 MBq (1.0 to 31.2 mCi) using 1 - 4 catheters has achieved an average dose of 268 Gy to tumor (n = 22). Significant correlations between patient survival and tumor treatment coverage / radiation absorbed doses to tumor has been found. The patients with lower treatment coverage or lower radiation absorbed doses (< 100 Gy mean tumor dose) (Group A), had an average survival of 5.3 ± 2.8 months (n = 10), which is similar to previously reported patient survival. In contrast, patients who received higher treatment coverage (> 70%) and higher absorbed dose (> 100 Gy), had an average survival of 18.0 ± 11.4 months (n = 12) until now, while 5 of them are still alive. The Group B had a significantly higher survival than Group A (P < 0.005). During this clinical trial, the use of tumor shape / volume-based planning and higher activities for tumor treatment, it has been achieved the better tumor coverage and more reproduced tumor treatment.
Conclusion: The therapy of recurrent GBM using 186RNL has seen a positive therapy effect, benefiting patient survival significantly. Image-based therapy evaluation and dosimetry (theranostics) will play an important role in predicting the effectiveness of the 186RNL therapy and patient survival, as well as the need for tumor re-treatment. Phase 2 / 3 clinical trial is expected to start in a few months.
Dosimetry of Intrathecally Administered ¹³¹I-Labeled Omburtamab for Compartmental Radioimmunotherapy
John L Humm¹, Milan Grkovski¹, Pat Zanzonico¹, Kim Kramer², and Neeta Pandit-Taskar³
Departments of ¹Medical Physics, ²Pediatrics, and ³Radiology, Memorial Sloan Kettering, New York
Purpose: To determine the radiation dose to the cerebrospinal fluid (CSF) compartment, a metastatic site for several cancers, from the radioiodine-labeled-B7-H3 targeting antibody omburtamab after intraventricular injection.
Methods: Two separate studies have been performed. In one, 42 patients were administered 71 ± 4 MBq of ¹²⁴I-labeled omburtamab one week prior to therapy. Whole-body PET images were acquired at approximately 4, 24 and 48 h post-intrathecal administration. In the second study, 95 patients received 75 ± 5 MBq of ¹³¹I-labeled omburtamab and gamma camera imaging performed at approx. 4, 24 and 48 h post injection. In both studies, serial CSF and peripheral blood samples were assayed. Dosimetry estimates were derived based on fitting and integration of exponential functions.
Results: ¹³¹I mean absorbed doses (cGy/MBq) from attenuation-corrected planar gamma camera images were 0.63 ± 0.38 for CSF, 1.03 ± 0.69 for ventricles, and 0.045 ± 0.032 for whole body. For comparison, median absorbed dose (cGy/MBq) projected from ¹²⁴I-omburtamab PET were 0.52 (CSF), 0.62 (ventricles) and 0.045 (whole body). Absorbed dose estimates derived from the CSF sample data were significantly higher than those based on imaging, likely due to local sampling from the Ommaya injection site and lack of rapid activity equilibration with the CSF compartment. Intra-thecal administration of radiolabeled ¹³¹I-omburtamab achieves high target-to-blood absorbed dose ratios allowing for administered activities of 1850-2960 MBq (50-80 mCi) while keeping the blood absorbed dose well below 200 cGy, the threshold for marrow radiotoxicity.
Conclusions: CSF dosimetry performed using serial planar images was in good agreement with the ¹²⁴I PET-derived dosimetry because of the high target-to-background image contrast resulting from intra-ventricular injection. Administration of ¹³¹I-omburtamab allows acceptable target-to-blood absorbed dose ratio.
Intra-arterial administration of receptor targeted agent, ⁹⁰Y-DOTATOC
Sandeep Laroia¹, Stephen A. Graves¹, Mark T. Madsen¹, M. Sue O’Dorisio², Yusuf Menda¹
Departments of ¹Radiology and ²Pediatrics, University of Iowa, Iowa City, Iowa
Purpose: Intraarterial (IA) administration of receptor-targeted radiopharmaceutical therapy (RPT) may offer a therapeutic advantage over intravenous (IV) administration in cases of localized or liver-dominant disease. The most common site of metastasis for neuroendocrine tumors (NETs) is liver, and therefore this population of patients may benefit from intraarterial liver-directed therapy with somatostatin analogues.
Methods: A theoretical model for determining the dosimetric advantage of IA-RPT administration based on first-order blood extraction kinetics was developed and analytically solved. A Phase I activity escalation study was initiated for IA administration of ⁹⁰Y-DOTATOC to patients with liver-dominant NETs, which were not amenable to other therapies (surgery, ablation) and have progressed after treatment with octreotide/lanreotide and/or other treatments (everolimus, sunitinib). (NCT03724409). Quantitative ⁹⁰Y-PET/CT imaging was performed at 48 hours post administration for renal and liver dose estimation.
Results: The theoretical model of IA-RPT suggests that tumor dosimetric advantage over IV administration depends strongly on arterial selectivity but not on single-pass extraction fraction. Three subjects were treated with increasing activities of ⁹⁰Y-DOTATOC, ranging from 2.96 GBq – 3.73 GBq. Renal dosimetry was consistent with prior experience with 90Y-DOTATOC – 1.48 ± 0.28 Gy/GBq estimated using the single time-point method (M. Madsen et al., Med. Phys. 45(5), 2018). Although single-timepoint dosimetry is not as well-established for liver and tumor, estimated dosimetry was favorable, approximately ~0.5 Gy/GBq and ~16 Gy/GBq respectively. No significant liver, renal, or bone marrow toxicity was observed in any subject.
Conclusions: Intraarterial administration of ⁹⁰Y-DOTATOC in patients with liver-dominant metastatic NETs has shown preliminary evidence of safety. Maximum tolerated activity has not yet been reached, and therefore further escalation is warranted.
Funding Support, Disclosures, and Conflict of Interest: NIH R01 CA235800-01A1. Role: Consultant / Medical Physicist NanoTx Inc: Share holder Plus Therapeutics Inc: Consultant
Not Applicable / None Entered.
Not Applicable / None Entered.