RESUMO
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.
RESUMO
BACKGROUND: Cystic echinococcosis (CE) caused by Echinococcus granulosus, significantly impacts health globally, but is a rare disease in Norway. CE is treated with a combination of anthelmintics and surgery, or percutaneous drainage. CASE PRESENTATION: A woman in her thirties underwent extensive surgery due to disseminated CE in the abdominal cavity and liver. Due to intraoperative cyst rupture with contamination of the abdominal cavity, peritoneal lavage with hypertonic saline (20 % NaCl), a scolicidal agent, was performed for ten minutes before irrigation with physiological saline. Immediately after surgery, the patient was haemodynamically unstable and did not awake. Blood level of sodium was found to be severely increased at 188 mmol/L (ref 137−144 mmol/L). Hypotonic fluids (5 % glucose) were immediately administered intravenously to correct the acute hypernatraemia. CT scan of the head did not show signs of bleeding or oedema. The sodium level was normalised on postoperative day three and the patient was discharged without any neurological sequelae. INTERPRETATION: Our patient developed iatrogenic acute severe hypernatraemia following abdominal lavage with hypertonic saline. Acute severe hypernatraemia is potentially lethal. Hypertonic saline must be used intraoperatively with great caution. Regular blood tests to detect hypernatraemia and monitor other electrolyte disturbances should be mandatory.
