High-Dose Samarium-153-EDTMP

Avid and specific skeletal and bone-forming tumor localization of samarium-153EDTMP allowed for a 30-fold dose escalation in osteosarcoma [44]. High-dose samarium-153-EDTMP, with or without chemotherapy, requires stem cell support because of the potential for prolonged thrombocytopenia, as shown by Turner et al. [45, 46]. High-dose samarium-153-EDTMP has been used by different investigators to treat osteosarcoma [41, 44, 47–50]. Although increased radiographic responses were seen using gemcitabine radiosensitization 1 day after samarium-153-EDTMP infusion, the durability of response against osteosarcoma metastases was not improved [47]. To summarize, it would appear that samarium-153-EDTMP is useful in the relatively limited osteosarcoma situations: (a) palliation of bone metastases,

(b) palliation of metastases of tumors that form bone (i.e., positive on bone scan), and

(c) in conjunction with external beam radiotherapy for control of unresectable osteosarcoma.

Advantages of Radium-223, an Alpha Particle Emitting Bone-Seeking Radiopharmaceutical Compared to the Beta Emitter, Samarium-153-EDTMP

Once a radionuclide is deposited in bone and/or in or near a cancer cell or tumor vessel in bone, the rate of rate of radioactive emissions (half-life), range, and energy of particle emissions (MeV) are quite different within the target zone for alpha versus beta emitters [51–54]. Energy, tissue penetration range, gamma camera imaging, and physical characteristics of these bone-seeking radiopharmaceuticals are a summarized in Tables 1, 2, and 3, respectively. Figure 1 depicts mass and energy characteristics of ionizing radiation (gamma rays, electrons or beta particles, protons, and alpha particles) as well as different type of DNA damage from the ionizing radiation particles. Figure 2 illustrates the radioactive decay cascade of radium-223.

All radium isotopes are unstable and decay to produce radiation. Prior experience with radium for treatment of cancer in the early twentieth century used radium-226 which has long half-life and significant safety problems associated with decay to long-lived radon daughters (i.e., radioactive radon gas) and off-target radiation side effects from radioactive radon (Fig. 3). Hence, the radium-226 isotope is now

Table 3 153Sm-EDTMP and Radium-223: physical characteristics

considered unsuitable for safe internal radiotherapy [55]. However, radium-223 has favorable decay characteristics: radon daughter decay is rapid (4 s), providing much less of a chance for “off target” radon diffusion (Fig. 3).

Preclinical studies of radium-223. Production and characterization of clinical grade radium-223 has been previously described in detail [55, 56]. Because radium-223 is an alkaline earth metal, it acts like calcium. The radium-223 isotope has been shown to specifically deposit alpha particles at sites inside the intended skeletal metastases and/or bone-forming osteosarcoma target lesions [56–60]. Preclinical studies in rodents with radium-223 showed avid skeletal deposition, relative sparing of the bone marrow, and nearly no soft tissue uptake [57, 61]. Extremely high doses of radium-223 in Balb c mice [1,250, 2,500, and 3,750 kBq/kg (25–75× the recommended monthly dose of 50 kBq/kg)] caused some effects on marrow, but the 4-week LD50 was not reached [62]. In this study, the greatest effect was on osteoblasts and osteocytes; it also confirmed marrow sparing and inability of the short-range alpha particles from radium-223 to completely ablate radiationsensitive hematopoietic stem cells.

Experience with radium-223 in a phase I [59] and a randomized phase II trial in men with metastatic prostate cancer confirmed excellent activity against bone metastases and a low toxicity profile (i.e., a high therapeutic index) [58–60, 63]. Using doses of 5, 25, 50, or 100 kBq/kg, a dose response relationship was seen in pain index at week 2 [60] and the highest dose group also had significantly decreased levels of alkaline phosphatase. Two-year follow-up of the phase II trial shows overall survival benefit of 65 weeks vs 46 weeks comparing radium-223 versus placebo (HR 0.476; cox regression p = 0.017). There were no long-term hematologic toxicities or secondary malignancies reported in this small phase II cohort (N = 33) [63]. Results of a randomized phase III, double-blind, placebo controlled trial of [2, 64] radium-223 in prostate cancer at a dose of 50 kBq/kg monthly × 6 and 2:1 randomization between active and placebo (N = 921) were presented at ASCO 2012 [64] and recently published in the New England Journal of Medicine. This study resulted

Fig. 1 Radioactive particle mass, energy, and DNA damage. Top: photons have no mass; protons have

¼ the mass energy of alpha particles. Thus, alpha particles have much greater mass and energy than electrons (beta particles). Bottom: Graphic representation of the high energy of alpha particles causing double strand breaks which are more difficult for cancer cells to repair than single stand breaks

in the FDA approval of radium-223 in May 2013. Compared to placebo radium-223 was associated with significantly improved overall survival (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95 % CI, 0.58–0.83; P < 0.001) and was also associated with prolonged time to first skeletal-related event (median 15.6 months

Fig. 2 Radium-223 decay cascade. On average, the initial ejection of the high LEt alpha particle takes a relatively long time (t1/2 11.4 days is almost a million seconds). Subsequent quick decay of unstable isotopes of radon (4 s), polonium (2 ms), lead (2,166 s) bismuth (130 s), and polonium or thallium isotopes (287 s) yields an additional three alpha particles + two beta particles in the same before the stable Pb-207 isotope is finally formed. Alpha particle emissions account for about 94 % of the emitted energy of radium-223. In 1 month (<3 half-lives) ~10 % of radioactivity remains; in 7 weeks (6 half-lives) only about 1/64 (<2 %) of initial radium-223 radioactivity remains

vs 9.8 months, respectively; HR = 0.658; 95 % CI, 0.522–0.830; p = 0.00037). Hematologic adverse events were uncommon (any grade 3 or 4 neutropenia in

2.2 % and 0.7 % and any grade 3 or 4 thrombocytopenia in 6.3 % and 2 % of the radium-223 and placebo groups, respectively). Although targeting of osteoblastic osteosarcoma tumors would expected to be much more specific than prostate cancer, currently this is an unlabeled use of the radiopharmaceutical.

At MD Anderson Cancer Center a single osteosarcoma patient with head, neck, and skull base osteosarcoma with skeletal metastases was provided 2 doses of radium-223 in December 2009 and January 2010 [65]. Decrease in alkaline phosphatase and improvement in pain for approximately 2 months was seen. Bone scan showing the clinical response of this patient is illustrated in Fig. 4. At MD Anderson Cancer Center, a phase I dose trial in osteosarcoma is open to accrual (clini- caltrials.gov # NCT01833520). The purpose is to determine safety of escalating doses of radium-223 in osteosarcoma patients with osteoblastic tumors as well as to determine best quantitative imaging to evaluate responses using Tc-99m-MDP Spect-CT, NaF-18 PET, and F-18 deoxyglucose.

Fig. 3 Safety of Radium-223 compared to other radium isotopes is graphically depicted. Radon (Rn) daughter decay is in red. The very short half-life of Rn daughter for radium-223 (4 s) limits amount of diffusion away from the targeted bone tumor deposition of radium-223. In contrast in the early twentieth century radium-226 was used clinically. This isotope was less safe and is no longer in clinical use because of the radon daughter t1/2 of 3.8 days resulted in off-target radiation side effects