Radium-223 dichloride in prostate cancer: proof of principle for the use of targeted alpha treatment in clinical practice.

PURPOSE: To summarise data with radium-223 dichloride (223RaCl2), a mechanism-mediated targeted alpha therapy (TAT), in metastatic castration-resistant prostate cancer (mCRPC) and to chart the development of TAT in mCRPC and in other tumour types. METHODS: Literature for this systematic review was identified using a PubMed search: ("targeted alpha therapy" or "targeted alpha particle therapy") or (213-bismuth or bismuth-213 or 213Bi) or (225-actinium or actinium-225 or 225Ac) or (211-astatine or astatine-211 or 211At) or (212-lead or lead-212 or 212Pb) or (227-thorium or thorium-227 or 227Th) or (223-radium or radium-223 or 223Ra or alpharadin) and (malignancy or cancer). Results were limited to English-language publications in humans, with the article type "clinical trial". RESULTS: Forty-one publications were included (30 from the literature search and 11 from manual searches/reviews). In clinical trials in mCRPC, 223RaCl2 monotherapy is well tolerated, with significantly longer overall survival than placebo and improved quality of life. Clinical trial data have been reinforced by findings from real-world studies. 223RaCl2 has also shown promise in other tumour types with bone metastases, including advanced breast cancer and advanced renal cell carcinoma (in combination with anti-vascular endothelial growth factor). Several astatine-211- and bismuth-213-labelled molecules have demonstrated anti-tumour activity and acceptable toxicity in other tumour types. CONCLUSIONS: 223RaCl2 has demonstrated "proof of concept" for use of TAT in cancer in clinical practice. The efficacy and safety of 223RaCl2 monotherapy have been demonstrated in mCRPC, and 223RaCl2 combination therapies are under investigation in various tumours. TAT has broad applicability across tumour types.

Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer.

BACKGROUND: It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS: At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS: A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS: Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Treatment of advanced differentiated thyroid carcinoma with high activity radioiodine therapy.

OBJECTIVES: This was a retrospective study to assess the efficacy and morbidity of high activity I therapy in patients with advanced differentiated thyroid carcinoma. METHODS: From 1975 to 2003, 38 patients with locally advanced or metastatic differentiated thyroid cancer (16 follicular, 20 papillary, one Hurthle cell, one insular) were treated with high activity radioiodine therapy (9 GBq) as the cancers had previously not responded to standard activities (5.5 GBq). RESULTS: Cumulative total activities received ranged from 11.8 to 84.5 GBq (mean 29.4 GBq per patient). Staging at presentation showed pT4 and/or M1 disease in 27/38 of patients (71.1%). Moderate (grade 2) and poorly differentiated (grade 3) tumours were present in a total of 9/38 patients (23.7%). Outcomes were evaluated according to the results of I whole-body scans, serum thyroglobulin, radiological assessments and physical examination. Neither [18F]flurodeoxyglucose positron emission tomography (F-FDG PET) nor 99mTc sestamibi were available during this study. The mean duration of follow-up was 83 months. A complete response was observed in 7/38 patients (18.4%), progressive disease in 27/38 (71.1%) and stable disease in 4/38 (10.5%). The mean survival from initiation of high activity treatment was 36.6 months. For patients with lung disease the mean survival was 45 months, neck disease 38.9 months, bone disease 35 months and multiple sites was 30.9 months. Twelve patients died during follow-up (10 due to thyroid carcinoma). After high activity treatment, 9.7% of patients suffered grade 3 and 3.2% suffered grade 4 WHO haematological toxicity. Significant salivary gland morbidity was observed (30% dry mouth, 27% salivary swelling). CONCLUSIONS: Repeated treatment with high activity (9 GBq) I in patients with advanced differentiated thyroid carcinoma appears to be of no apparent benefit and may lead to late morbidity.