ABSTRACT
Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). With a median time to recurrence of 11-12 months, there is a need for novel therapies. Radspherin® consists of the α-emitting radionuclide radium-224 (224Ra), which has a half-life of 3.6 days and is adsorbed to a suspension of biodegradable calcium carbonate microparticles that are designed to give short-range radiation to the serosal peritoneal surface linings, killing free-floating and/or tumor cell clusters that remain after CRS-HIPEC. Methods: A first-in-human phase 1 study (EudraCT 2018-002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin® was administered intraperitoneally 2 days after CRS-HIPEC. Dose escalation at increasing activity dose levels of 1-2-4-7-MBq, a split-dose repeated injection, and expansion cohorts were used to evaluate the safety and tolerability of Radspherin®. The aim was to explore the recommended dose and biodistribution using gamma-camera imaging. The results from the planned safety interim analysis after the completion of the dose-limiting toxicity (DLT) period of 30 days are presented. Results: Twenty-three patients were enrolled: 14 in the dose escalation cohort, three in the repeated cohort, and six in the expansion cohort. Of the 23 enrolled patients, seven were men and 16 were women with a median age of 64 years (28-78). Twelve patients had synchronous PM stage IV and 11 patients had metachronous PM [primary stage II; (6) and stage III; (5)], with a disease-free interval of 15 months (3-30). The peritoneal cancer index was median 7 (3-19), operation time was 395 min (194-515), and hospital stay was 12 days (7-37). A total of 68 grade 2 adverse events were reported for 17 patients during the first 30 days; most were considered related to CRS and/or HIPEC. Only six of the TEAEs were evaluated as related to Radspherin®. One TEAE, anastomotic leakage, was reported as grade 3. Accordion ≥3 grade events occurred in a total of four of the 23 patients: reoperation due to anastomotic leaks (two) and drained abscesses (two). No DLT was documented at the 7 MBq dose level that was then defined as the recommended dose. The biodistribution of Radspherin® showed a relatively even peritoneal distribution. Conclusion: All dose levels of Radspherin® were well tolerated, and DLT was not reached. No deaths occurred, and no serious adverse events were considered related to Radspherin®.Clinical Trial Registration: Clinicaltrials.gov, NCT03732781.
ABSTRACT
Aim: Two ongoing phase I studies are investigating the use of radium-224 adsorbed to calcium carbonate micro particles (224Ra-CaCO3-MP) to treat peritoneal metastasis originating from colorectal or ovarian cancer. The aim of this work was to study the level of radiation exposure from the patients to workers at the hospital, carers and members of the public. Method: Six patients from the phase 1 trial in patients with colorectal cancer were included in this study. Two days after cytoreductive surgery, they were injected with 7 MBq of 224Ra-CaCO3-MP. At approximately 3, 24 and 120 h after injection, the patients underwent measurements with an ionization chamber and a scintillator-based iodide detector, and whole body gamma camera imaging. The patient was modelled as a planar source to calculate dose rate as a function of distance. Scenarios varying in duration and distance from the patient were created to estimate the potential effective doses from external exposure. Urine and blood samples were collected at approximately 3, 6, 24, 48 and 120 h after injection of 224Ra-CaCO3-MP, to estimate the activity concentration of 224Ra and 212Pb. Results: The patients' median effective whole-body half-life of 224Ra-CaCO3-MP ranged from 2.6 to 3.5 days, with a mean value of 3.0 days. In the scenarios with exposure at the hospital (first 8 days), sporadic patient contact resulted in a range of 3.9-6.8 µSv per patient, and daily contact resulted in 4.3-31.3 µSv depending on the scenario. After discharge from the hospital, at day 8, the highest effective dose was received by those with close daily contact; 18.7-83.0 µSv. The highest activity concentrations of 224Ra and 212Pb in urine and blood were found within 6 h, with maximum values of 70 Bq/g for 224Ra and 628 Bq/g for 212Pb. Conclusion: The number of patients treated with 224Ra-CaCO3-MP that a single hospital worker - involved in extensive care - can receive per year, before effective doses of 6 mSv from external exposure is exceeded, is in the order of 200-400. Members of the public and family members are expected to receive well below 0.25 mSv, and therefore, no restrictions to reduce external exposure should be required.
