223-Radium for metastatic osteosarcoma: combination therapy with other agents and external beam radiotherapy

Abstract

BackgroundBone-seeking radiopharmaceuticals can deposit radiation selectively to some osteosarcoma tumours because of the bone-forming nature of this cancer.ObjectivesThis is the first report of using 223-radium, an alpha-emitting calcium analogue with a high therapeutic index, in combination therapy with other agents in 15 patients with metastatic osteoblastic osteosarcoma.MethodsCandidates for alpha-radiotherapy if 99mTc-MDP bone scan had avid bone-forming lesions and no therapy of higher priority (eg, definitive surgery). Monthly 223-radium infusions (1.49 μCi/kg or 55.13 kBq/kg) were given.ResultsThe median infusion number was three and the average time to progression was 4.3 months for this cohort receiving 223-radium+other agents. Agents provided during 223-radium included (1) drugs to reduce skeletal complications: monthly denosumab (n=13) or zolendronate (n=1); (2) agents with antivascular endothelial growth factor activity, pazopanib (n=8) or sorafenib (n=1), (3) alkylating agents: oral cyclophosphamide (n=1) or ifosfamide, given as a 14-day continuous infusion (n=1, two cycles), (4) high-dose methotrexate (n=1), pegylated liposomal doxorubicin (n=1); and (5) two other combinations: nivolumab and everolimus (n=1) and rapamycin and auranofin (n=1). Radiation therapy, including stereotactic body radiotherapy (SBRT), was also given to 11 patients concurrently with 223-radium (n=2), after 223-radium completion (n=3), or both concurrently and then sequentially for other sites (n=6). After 223-radium infusions, patients without RT had a median overall survival of 4.3 months compared with those with SBRT and/or RT, who had a median overall survival of 13.5 months.Conclusion Although only 1/15 of patients with osteoblastic osteosarcoma still remain alive after 223-radium, overall survival

Future Directions in the Treatment of Osteosarcoma

“…Beyond ifosfamide and etoposide, the rational selection of agents to further modify adjuvant chemotherapy remains difficult. There are limited active treatments for patients with metastatic disease, including ifosfamide-etoposide (IE) [ 44 ], single agent ifosfamide [ 40 , 42 , 43 ], regorafenib [ 45 ], gemcitabine-docetaxel [ 46 ], cabozantinib [ 47 ], pazopanib [ 48 ] ± SBRT [ 49 ] and radium-223 alone or in combination [ 50 , 51 ]. Given the modest response rates to therapies beyond ifosfamide ± etoposide, a thoughtful, likely translational, approach is needed to identify new therapies with a high likelihood of success.…”

Trends in Tumor Site-Specific Survival of Bone Sarcomas from 1980 to 2018: A Surveillance, Epidemiology and End Results-Based Study

“…Radiotherapy is effective in some of the selected osteosarcoma patients. In addition, alpha emitter radium-223 can be a new radiation option for metastatic osteosarcoma but is just reported in some clinical cases [25,26]. It still takes a long time to develop radiotherapy to generally improve the survival of osteosarcoma patients.…”

Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks

“…In a long-term follow-up study of the same patient cohort, the authors reported disease stabilisation in seven of the 10 patients, with a median progression-free survival of 107.7 months (range 47.2e111.4 months) versus 26.2 months (range 13.8e75.9 months) for patients with meningioma progression [63]. Anderson et al [64] reported the first use of radium-223 for osteoblastic bone metastases from osteosarcoma in a series of 15 patients. As well as radium-223 (55.13 kBq/kg per cycle, up to six cycles), 12 patients received stereotactic body radiotherapy (SBRT; mean dose, 40 Gy in five fractions) or other EBRT (45 Gy in 15 fractions) either concurrently, concurrently and sequentially or sequentially.…”