Purpose: Various radiation therapy (RT) dose/fractionation schedules are acceptable for palliation in multiple myeloma. Nine years of single-institution RT experience were reviewed to determine the influence of dose/fractionation and other factors pertinent to individualizing therapy. Methods and Materials: In total, 152 items were identified from Current Procedural Terminology codes for multiple myeloma treatment from 2012 through June 30, 2021. After exclusions, 205 sites of radiation in 94 patients were reviewed. Data were captured from treatment planning and clinical records. To statistically assess the association between biological effective dose (BED10) and variables of interest, BED was first dichotomized to <24 Gy versus ≥24 Gy. Multivariate analysis used SAS software and a generalized estimating equation approach to account for multiple observations per patient. Results: Fractions of 1.8 to 8 Gy were used in 1 to 25 fractions. Most patients had no significant toxicity. Grade 1 toxicity was more likely with greater BED radiation courses, as expected (20% vs 12% for BED <24 Gy). Pain relief was complete or very good for most sites, with <3% reporting no pain relief. Eleven sites in 9 patients required retreatment. All retreatment sites had palliation that was lasting, with a median of 22 months to last follow-up or death after repeat course (range, 0.5-106 months). There was a trend for better pain control and less risk of fracture retreatment with BED ≥24 Gy. Conclusions: Most patients had good palliation without toxicity. BED ≥24 Gy caused 8% greater risk of grade 1 toxicity and trended toward better pain control plus reduced risk of fracture retreatment.

TPS7069 Background: Older adults with ALL have poor survival outcomes. Although aHSCT can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status, and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative aHSCT. The 1-year disease free survival (DFS) for patients ≥ 40 years who receive an aHSCT for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of TBI-based regimens in adults with ALL when combined with cyclophosphamide (Cy). Reduced intensity conditioning for ALL patients has fallen out of favor due to high relapse rate forfeiting the benefit of reduced NRM. High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI (12 Gy) is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing aHSCT, but with less NRM confering survival benefit over Cy/TBI 12 Gy. Methods: This study is a single center, single-arm phase II clinical trial of Flu 40 mg/m2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. Patients aged 40-65 years with ALL in CR, KPS ≥ 70, adequate organ function, and having HLA-matched sibling or unrelated donor will be eligible. The primary endpoint of the study is 1-year DFS post-transplant. Secondary endpoints include 1-year overall survival (OS), incidence and severity of acute and chronic GVHD, immune reconstitution and regimen related toxicity. The study has just finished accrual (January 2019) enrolling a total of 16 patients. This number of patients was pre-determined to give a probability ≤ 0.05 of concluding that the 1-year DFS rate exceeds 45%, and a probability of at least 0.80 of concluding that the 1-year DFS rate exceeds 45% (expecting 1-year DFS of 75%). Clinical trial information: NCT01991457.

In 2017, the American Society for Radiation Oncology (ASTRO) board of directors prioritized radiopharmaceutical therapy (RPT) as a leading area for new therapeutic development, and the ASTRO RPT workgroup was created. Herein, the workgroup has developed a framework for RPT curriculum development upon which education leaders can build to integrate this modality into radiation oncology resident education. Through this effort, the workgroup aims to provide a guide to ensure robust training in an emerging therapeutic area within the context of existing radiation oncology training in radiation biology, medical physics, and clinical radiation oncology. The framework first determines the core RPT knowledge required to select patients, prescribe, safely administer, and manage related adverse events. Then, it defines the most important topics for preparing residents for clinical RPT planning and delivery. This framework is designed as a tool to supplement the current training that exists for radiation oncology residents. The final document was approved by the ASTRO board of directors in the fall of 2021. (C) 2022 Elsevier Inc. All rights reserved.

Radiopharmaceutical therapy (RPT) continues to demonstrate tremendous potential in improving the therapeutic gains in radiation therapy by specifically delivering radiation to tumors that can be well assessed in terms of dosimetry and imaging. Dosimetry in external beam radiation therapy is standard practice. This is not the case, however, in RPT. This NRG (acronym formed from the first letter of the 3 original groups: National Surgical Adjuvant Breast and Bowel Project, the Radiation Therapy Oncology Group, and the Gynecologic Oncology Group)-National Cancer Institute Working Group review describes some of the challenges to improving RPT. The main priorities for advancing the field include (1) developing and adopting best practice guidelines for incorporating patient-specific dosimetry for RPT that can be used at both large clinics with substantial resources and more modest clinics that have limited resources, (2) establishing and improving strategies for introducing new radiopharmaceuticals for clinical investigation, (3) developing approaches to address the radiophobia that is associated with the administration of radioactivity for cancer therapy, and (4) solving the financial and logistical issues of expertise and training in the developing field of RPT.

Purpose: One-year monitoring of patients receiving intraperitoneal (IP) Pb-212-TCMC-trastuzumab to provide long-term safety and outcome data. A secondary objective was to study 7 tumor markers for correlation with outcome. Methods: Eighteen patients with relapsed intra-abdominal human epidermal growth factor receptor-2 expressing peritoneal metastases were treated with a single IP infusion of Pb-212-TCMC-trastuzumab, delivered <4h after 4mg/kg IV trastuzumab. Seven tumor markers were studied for correlation with outcome. Results: Six dose levels (7.4, 9.6, 12.6, 16.3, 21.1, 27.4MBq/m(2)) were well tolerated with early possibly agent-related adverse events being mild, transient, and not dose dependent. These included asymptomatic, abnormal laboratory values. No late renal, liver, cardiac, or other toxicity was noted up to 1 year. There were no clinical signs or symptoms of an immune response to Pb-212-TCMC-trastuzumab, and assays to detect an immune response to this conjugate were negative for all tested. Tumor marker studies in ovarian cancer patients showed a trend of decreasing Cancer antigen 72-4 (CA 72-4) aka tumor-associated glycoprotein 72 (TAG-72) and tumor growth with increasing administered radioactivity. Other tumor markers, including carbohydrate antigen (CA125), human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and carcinoembryonic antigen (CEA) did not correlate with imaging outcome. Conclusions: IP Pb-212-TCMC-trastuzumab up to 27MBq/m(2) seems safe for patients with peritoneal carcinomatosis who have failed standard therapies. Serum TAG-72 levels better correlated to imaging changes in ovarian cancer patients than the more common tumor marker, CA125.

Purpose: Dosimetric comparison was performed of radiation methods for target coverage and non-target sparing in palmar fibrosis (i.e., Dupuytren disease).Most early stage disease has been treated with superficial radiation using standard cones and shielding of uninvolved areas.With clinical set up, no information regarding depth of the nodules or percent coverage of the target was obtained.With concern for late effects of radiation used to treat a benign condition and declining availability of superficial radiation equipment, we compared dosimetry of superficial radiation versus patient specific electron therapy.Methods: One female patient (thinner hand) and one male patient were selected for intra-patient range in a CT dosimetric comparison of 6-MeV electrons ± bolus versus 90kV photons.The clinically set up target volume (CTV) included cords/nodules plus 1-2 cm margin.The posterior hand avoidance was defined as the tissues posterior to the ventral border of the metacarpal bones.Results: Normalized to 90% of the prescribed dose, 6-MeV electrons ± bolus achieved 100% coverage of CTV.The dose maximum as well as dose to the posterior hand avoidance was reduced by bolus.The 90% isodose line with the superficial radiotherapy was 0.4 cm depth and achieved 73-75% CTV coverage.Conclusions: 6-MeV electrons with individualized bolus gave superior CTV coverage over superficial radiotherapy at the 90% isodose lines, with relative sparing of normal tissues.

PURPOSE:To determine if temozolomide reduces the risk of distant brain failure (DBF, metachronous brain metastases) in patients with 1 to 4 brain metastases treated with radiosurgery without whole-brain radiation therapy (WBRT).METHODS AND MATERIALS:Twenty-five patients with newly diagnosed brain metastases were enrolled in a single institution phase 2 trial of radiosurgery (15-24 Gy) and adjuvant temozolomide. Temozolomide was continued for a total of 12 cycles unless the patient developed DBF, unacceptable toxicity, or systemic progression requiring other therapy.RESULTS:Twenty-five patients were enrolled between 2002 and 2005; 3 were not evaluable for determining DBF. Of the remaining 22 patients, tumor types included non-small cell lung cancer (n = 8), melanoma (n = 7), and other (n = 7). Extracranial disease was present in 10 (45%) patients. The median number of tumors at the time of radiosurgery was 3 (range, 1-6). The median overall survival was 31 weeks. The median radiographic follow-up for patients who did not develop DBF was 33 weeks. Six patients developed DBF. The 1-year actuarial risk of DBF was 37%.CONCLUSIONS:In this study, there was a relatively low risk of distant brain failure observed in the nonmelanoma subgroup receiving temozolamide. However, patient selection factors rather than chemotherapy treatment efficacy are more likely the reason for the relatively low risk of distant brain failure observed in this study. Future trial design should account for these risk factors.

To determine the toxicity and recommended dose for pre-operative (pre-op) stereotactic radiosurgery (SRS) in management of brain metastases and the rate of subsequent leptomeningeal disease (LMD). Twenty newly diagnosed brain metastasis patients were enrolled into a phase I dose escalation/de-escalation trial between 01/2011 and 11/2015. Eligible patients included those with operable (≤4) metastases (other than SCLC/lymphoma) measuring 2-6cm in maximum diameter, age >19yo, KPS ≥60, life expectancy >12 weeks. Patients were divided into two cohorts (Group A: 2-4cm [n=11], Group B: >4-6cm [n=9]), with starting dose level for Groups A and B of 15Gy and 12Gy, respectively. All patients had surgical resection within 30 days of SRS. Toxicity was recorded using CTCAEv4.0. Dose-limiting toxicity (DLT) was defined as any grade ≥3 seizure, wound complication, or somnolence; any grade ≥4 neurologic/dermatologic event; any grade 5 event within 30 days of surgery. Serious adverse events were defined as death or treatment-related prolonged (>5 days) or new hospitalization. LMD was defined as diffuse carcinomatosis and/or distant focal pachymeningeal (dural) tumor within the 1-year study period. All patients had a gross total resection. For Group A, two DLTs occurred at the 15Gy level (grade 3 wound complication/CSF leak requiring surgery). No DLT was noted in the initial cohort (n=3) of Group B at 12Gy and dose was escalated to 15Gy (n=6) with no DLT. Other acute therapy-related toxicities included grade 2 nausea/vomiting (n=1), grade 3 pseudomeningocele requiring shunt (n=1), and grade 3 hemorrhage requiring craniotomy (n=1). No grade ≥4 toxicity occurred. Within the first year of follow up, one patient developed LMD. Pre-op SRS is feasible with doses as high as 15Gy for targets as large as 6cm and associated with a low LMD rate. Larger studies are required to determine the optimal sequence of SRS and surgery.

Purpose: To support the phase I trial for toxicity, biodistribution and pharmacokinetics of intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. A whole body gamma camera imaging method was developed for estimating amount of 212Pb-TCMC-trastuzumab left in the peritoneal cavity. Methods: 212Pb decays to 212Bi via beta emission. 212Bi emits an alpha particle at an average of 6.1 MeV. The 238.6 keV gamma ray with a 43.6% yield can be exploited for imaging. Initial phantom was made of saline bags with 212Pb. Images were collected for 238.6 keV with a medium energy general purpose collimator. There are other high energy gamma emissions (e.g. 511keV, 8%; 583 keV, 31%) that penetrate the septae of the collimator and contribute scatter into 238.6 keV. An upper scatter window was used for scatter correction for these high energy gammas. Results: A small source containing 212Pb can be easily visualized. Scatter correction on images of a small 212Pb source resulted in a ∼50% reduction in the full width at tenth maximum (FWTM), while change in full width at half maximum (FWHM) was <10%. For photopeak images, substantial scatter around phantom source extended to > 5 cm outside; scatter correction improved image contrast by removing this scatter around the sources. Patient imaging, in the 1st cohort (n=3) showed little redistribution of 212Pb-TCMC-trastuzumab out of the peritoneal cavity. Compared to the early post-treatment images, the 18-hour post-injection images illustrated the shift to more uniform anterior/posterior abdominal distribution and the loss of intensity due to radioactive decay. Conclusion: Use of medium energy collimator, 15% width of 238.6 keV photopeak, and a 7.5% upper scatter window is adequate for quantification of 212Pb radioactivity inside peritoneal cavity for alpha radioimmunotherapy of ovarian cancer. Research Support: AREVA Med, NIH 1UL1RR025777-01

Objectives: To study the safety, dosimetry, and immunogenicity of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER2-expressing ovarian cancer and other malignancies.

The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on 177Lu (lutetium) and its application in radiopharmaceutical therapy.

283 Objectives To determine the long term safety of salvage intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. Methods 212Pb-TCMC-trastuzumab was delivered IP Results Sixteen patients at five dose levels (7.4, 9.6, 12.6, 16.3, 21.1 MBq/m2) were monitored up to for 1 year (10-11mo for. #14,#15) or until death. There were no clinical signs or symptoms of an immune response, and assays to detect an immune response to 212Pb-TCMC-trastuzumab were negative for all 13 of 16 tested (no sample for 3 patients). Most adverse events were related to disease or medications other than the 212Pb-TCMC-trastuzumab. Patients tolerated therapy at 7-21 MBq/m2 with minimal, asymptomatic laboratory abnormality (transient Grade 1 in 5/16 patients). Whereas hematologic toxicity has been dose-limiting in prior IP radionuclide conjugate studies, the mean platelet counts, total white blood cell counts and neutrophil counts remained normal after a mean equivalent dose to marrow of 0.006cGy/MBq. Only 2 patients had a transient decreased counts to Grade 1(Platelets 142,000/µL, WBC 3500/ µL without neutropenia). No late cardiac, liver or renal toxicity was found. Conclusions Five dose levels of IP 212Pb-TCMC-trastuzumab appear safe for patients with peritoneal carcinomatosis who have failed standard therapies. Monitoring up to 1 year showed minimal, transient toxicity within 6 weeks and no late toxicity. Research Support AREVA Med, and NIH 1UL1RR025777-01

OBJECTIVE Assess interaction of pazopanib, an oral antivascular endothelial growth factor inhibitor, with radiation in tumor xenograft models. METHODS Flank xenografts in female athymic nude mice of human lung cancer cell line, A549, and head and neck cancer cell line, UM-SCC-6, were allowed to grow to ∼5×5 mm. Groups were then treated with pazopanib and/or escalating doses of radiation and tumor measurements over time compared with untreated tumor-bearing controls. Pazopanib (100 mg/kg) began 7 days before radiation and continued for 28 days. Daily radiation was 0.5, 1, 2, or 3 Gy ×5 days. RESULTS Tumors in the A549 control group reached >4× the original size by day 36 postradiation. All treatment groups had less robust tumor growth (p<0.05) and the group receiving pazopanib+3 Gy radiation/day had tumor regression to less than baseline. In the UM-SCC-6-tumor-bearing animals, tumors in all treatment groups had less robust growth than untreated controls after day 23 post-treatment. CONCLUSION The combination of pazopanib and radiation resulted in a trend of superior tumor growth inhibition compared with either agent alone. All treatment groups had impaired tumor progression compared with untreated controls.

Our purpose was to study the safety, distribution, pharmacokinatics, immunogenicity, and tumor response of intraperitoneal Pb-212-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2) expressing malignancy. Methods: In a standard 3 + 3 phase 1 design for dose escalation, Pb-212-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies. Results: Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m(2)) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n = 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time). Non decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5 mu Sv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative. Conclusion: Five dose levels of intraperitoneal Pb-212-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.

638 Objectives To study toxicity, biodistribution, and pharmacokinetics of intra-peritoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2 expressing malignancy. This phase I trial provides IP therapy for patients with peritoneal carcinomatosis who have failed standard therapies. Methods 212Pb-TCMC-trastuzumab was delivered IP Results Four dose levels (7.4, 9.6, 12.6, 16.3 MBq/m2) have shown minimal toxicity at >1 year for 1st group & >2-10 mo for others. Imaging and pharmacokinetics in the 1st cohort (n=3) showed little redistribution of radioactivity out of the peritoneal cavity, no significant uptake in major organs and serum levels 2-12 mo. Conclusions Four dose levels of IP 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed minimal distribution outside the peritoneal cavity and good tolerance with minimal related toxicity. Research Support AREVA Med, NIH 1UL1RR025777-01

Our purpose was to study the safety, distribution, pharmacokinetics, immunogenicity, and tumor response of intraperitoneal 212Pb-TCMC-trastuzumab (TCMC is S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane) in patients with human epidermal growth factor receptor type 2 (HER-2)–expressing malignancy. Methods: In a standard 3 + 3 phase 1 design for dose escalation, 212Pb-TCMC-trastuzumab was delivered intraperitoneally less than 4 h after administration of trastuzumab (4 mg/kg intravenously) to patients with peritoneal carcinomatosis who had failed standard therapies. Results: Five dosage levels (7.4, 9.6, 12.6, 16.3, and 21.1 MBq/m2) showed minimal toxicity at more than 1 y for the first group and more than 4 mo for others. The lack of substantial toxicity was consistent with the dosimetry assessments (mean equivalent dose to marrow, 0.18 mSv/MBq). Radiation dosimetry assessment was performed using pharmacokinetics data obtained in the initial cohort (n = 3). Limited redistribution of radioactivity out of the peritoneal cavity to circulating blood, which cleared via urinary excretion, and no specific uptake in major organs were observed in 24 h. Maximum serum concentration of the radiolabeled antibody was 22.9% at 24 h (decay-corrected to injection time) and 500 Bq/mL (decay-corrected to collection time). Non–decay-corrected cumulative urinary excretion was 6% or less in 24 h (2.3 half-lives). Dose rate measurements performed at 1 m from the patient registered less than 5μSv/h (using portable detectors) in the latest cohort, significantly less than what is normally observed using nuclear medicine imaging agents. Antidrug antibody assays performed on serum from the first 4 cohorts were all negative. Conclusion: Five dose levels of intraperitoneal 212Pb-TCMC-trastuzumab treatment of patients with peritoneal carcinomatosis showed little agent-related toxicity, consistent with the dosimetry calculations.

Purpose: Study distribution, pharmacokinetics, and safety of intraperitoneal (IP) 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy. Experimental Design: IP 212Pb-TCMC-trastuzumab was delivered, after 4 mg/kg intravenous (IV) trastuzumab, to 3 patients with HER-2-expressing cancer who had failed standard therapies. Patients were monitored for toxicity and pharmacokinetics/dosimetry parameters. Results: Imaging studies after 0.2 mCi/m2 (7.4 MBq/m2) show little redistribution out of the peritoneal cavity and no significant uptake in major organs. Peak blood level of the radiolabeled antibody, determined by decay corrected counts, was <23% injected dose at 63 hours; maximum blood radioactivity concentration was 6.3nCi/mL at 18 hours. Cumulative urinary excretion was ≤6% in 2.3 half-lives. The maximum external exposure rate immediately post-infusion at skin contact over the abdomen averaged 7.67 mR/h and dropped to 0.67 mR/h by 24 hours. The exposure rates at the other positions monitored (axilla, chest, and femur) decreased as a function of distance from the abdomen. The data points correlate closely with 212Pb physical decay (T1/2=10.6 hours). Follow-up >6 months showed no evidence of agent-related toxicity. Conclusions: Pharmacokinetics and imaging after 0.2 mCi/m2 IP 212Pb-TCMC-trastuzumab in patients with HER-2-expressing malignancy showed minimal distribution outside the peritoneal cavity, ≤6% urinary excretion, and good tolerance.