Larsen Stein Gunnar, Graf Wilhelm, Mariathasan Anthony Burton, Sørensen Olaf, Spasojevic Milan, Goscinski Mariusz Adam, Selboe Silje, Lundstrøm Nadja, Holtermann Anne, Revheim Mona-Elisabeth, Bruland Øyvind Sverre
Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Front Med (Lausanne). 2023 Mar 1;10:1070362. doi: 10.3389/fmed.2023.1070362. eCollection 2023.
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 (Ra), 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.
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.
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.
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®. Clinicaltrials.gov, NCT03732781.
尽管进行了广泛的细胞减灭术和腹腔内热灌注化疗（CRS-HIPEC），结直肠癌的腹膜转移（PM）预后仍很差。复发的中位时间为11至12个月，因此需要新的治疗方法。Radspherin®由发射α粒子的放射性核素镭-224（Ra）组成，其半衰期为3.6天，吸附在可生物降解的碳酸钙微粒悬浮液上，旨在对浆膜腹膜表面进行短程辐射，杀死CRS-HIPEC后残留的游离漂浮和/或肿瘤细胞团。
在两个专门的CRS-HIPEC中心进行了一项首次人体1期研究（欧洲临床试验数据库编号：2018-002803-33）。在CRS-HIPEC术后2天腹腔内给予Radspherin®。采用1-2-4-7-MBq递增活度剂量水平、分剂量重复注射和扩大队列进行剂量递增，以评估Radspherin®的安全性和耐受性。目的是使用γ相机成像探索推荐剂量和生物分布。给出了在30天的剂量限制毒性（DLT）期结束后计划的安全性中期分析结果。
共纳入23例患者：剂量递增队列14例，重复队列3例，扩大队列6例。在纳入的23例患者中，男性7例，女性16例，中位年龄64岁（28-78岁）。12例患者为同步PM-IV期，11例患者为异时性PM[原发II期；（6例）和III期；（5例）]，无病间期为15个月（3-30个月）。腹膜癌指数中位数为7（3-19），手术时间为395分钟（194-515分钟），住院时间为12天（7-37天）。在最初30天内，17例患者共报告了68例2级不良事件；大多数被认为与CRS和/或HIPEC有关。只有6例治疗期间出现的不良事件被评估为与Radspherin®有关。1例治疗期间出现的不良事件，即吻合口漏，报告为3级。23例患者中共有4例发生了≥3级事件：因吻合口漏（2例）和引流脓肿（2例）再次手术。在7 MBq剂量水平未记录到DLT，该剂量水平随后被定义为推荐剂量。Radspherin®的生物分布显示腹膜分布相对均匀。
Radspherin®的所有剂量水平耐受性良好，未达到DLT。未发生死亡，且未发现严重不良事件与Radspherin®有关。Clinicaltrials.gov，NCT03732781。
