One would hope that survival data from at least one more phase III or phase IV clinical trial will convincingly show a prolongation of survival due to treatment with Alpharadin. This will not be inexpensive therapy.
Dr. Cheetham and Dr. Petrylak have provided a most helpful review of the available data on use of radium-223 dichloride (223RaCl2), known as Alpharadin, in the treatment of osteoblastic metastatic prostate carcinoma. A technique for separating the daughter 223Ra from the parent 227Ac has been developed at the Department of Energy Hanford Site, Office of National Isotope Programs.[1,2] Alpharadin appears to be the first bone-seeking radiopharmaceutical to prolong the life span; the beta-emitting bone seekers (rhenium-186 HEDP [186Re-HEDP], rhenium-188 HEDP [188Re-HEDP], samarium-153 lexidronam [153Sm-lexidronam], and strontium-89 chloride [89SrCl2] do not.
Life prolongation by Alpharadin is presumably due to the greater local cytocidal capability of its alpha-particle emission. The alpha particle is a helium nucleus containing two protons and two neutrons; it carries a 2+ charge, and it has about 7300 times the mass of a beta particle or electron (carrying a 1− charge). The size of the alpha particle, its charge (leading to interactions with nearby electrons), and its low velocity limit the distance it can travel before transferring all of its energy to nearby molecules. This conceptualization is called the linear energy transfer, or LET, and focuses on the rate of energy transfer by a particle to its surroundings, measured in keV/µm of track length. For the alpha particle, the LET is high, since the track length is quite short, averaging 0.05 to 0.10 mm or about 5 to 10 cell diameters. In some experimental systems, the alpha particle produces as much as 20 times as much biological damage as an equivalent radiation exposure from an electron or beta particle, and thus has a relative biological effectiveness (RBE) of 20. Because of the conservation of momentum, the recoil of the 223Ra daughter 219Rn, as it emits that alpha particle, may well raise the RBE to an even greater degree.
However, the mean beta-particle pathways in tissue from 186Re (1.1 mm), 188Re (2.7 to 3.1 mm), 153Sm (0.6 mm), and 89Sr (2.4 mm) are much longer than that of the alpha particle of 223Ra. This theoretically results in lesser degrees of biological damage at the site of emission around the osteoblastic metastasis than that produced by the alpha particle, but much greater damage (eg, myelosuppression) within a few millimeters (far beyond the path length of the alpha particle). The alpha-emitter should yield more local damage to osteoblastic metastases at the 223Ra deposition site and therefore more tumoricidal effect in this system per unit of radiation emitted. Alpharadin can, however, cause grade 3 and 4 neutropenia and leukopenia, directly related to the administered activity, because marrow and its stem cells reproduce and mature around bony trabeculae, where osteoblastic activity, and hence radiotracer deposition, is relatively high. Furthermore, the bone-seeking beta-emitters also have tumoricidal effects, resulting in a significant fall in the level of serum tumor markers, eg, prostate-specific antigen (PSA) and markers of bone metabolism.
Gastrointestinal side effects are virtually unknown with the beta-emitting radiotracers, of which only 89Sr is a calcium analog like 223Ra. Calcium is excreted in the intestine and resorption is under hormonal control. The calcium analog 223Ra is cleared by the intestine as well, and the effect of short-ranged 223Ra alpha emissions on intestinal mucosa probably explain the nausea, vomiting, and diarrhea not observed with the bone-seeking beta-emitters. Radiation-induced nausea and vomiting begin when the intestine receives a dose of 1 to 2 Gy, and intestinal damage is so severe at doses exceeding 12 Gy that death is inevitable.
A randomized trial of Alpharadin has shown a survival advantage for this radiopharmaceutical of 19 weeks (4.4 months) over placebo in a phase II study employing four IV injections of 50 kBq/kg every 4 weeks. In a 2011 study presented but not yet published (as of early 2012), however, the survival advantage was only 2.8 months. Cheetham and Petrylak conjecture that this survival increment of 2.8 months might actually have been greater because the study was stopped early; perhaps with more time to observe patients in the latter study, this survival advantage might have decreased even more from the earlier observation of 4.4 months. Favoring a true effect of Alpharadin is the delay in the time to first skeletal-related events of 5.2 months in the group receiving 223Ra.
The crucial double-blind randomized study would assess Alpharadin vs one of the beta-emitting bone seekers in this group of prostate cancer patients with bone metastases, to determine if there is any significant difference between the alpha- and beta-emitting radiopharmaceuticals in altering survival or the degree of pain relief. This will be expensive. Few, if any, randomized double-blind studies have even been performed comparing the several beta-emitting bone-seeking radiotracers because of the high cost and apparent unwillingness of manufacturers to fund these trials.
The beta-emitting radiotracers alluded to above have been used primarily to alleviate bone pain. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 questionnaire was the instrument employed by the Alpharadin researchers to study bone pain. However, this 30-item tool has only two questions in which the word “pain” appears, many more concerning activities of daily life (ADL), and none mentioning changes in analgesic medication. The group from University Hospital Utrecht have introduced a valuable scale to measure effects of therapy on bone pain, combining the interactive triad of (1) the level of pain with (2) changes in ADL and (3) alterations of analgesic drug dose, all of which must be considered before assuming that observed changes in pain perception are caused by the analgesic therapy under study. While these three dimensions of measuring responses to pain reduction by Alpharadin are recognized in a very recent report from the Karolinska Group, in which up to 71% pain reduction was noted at the highest dosage employed, 100 kBq/kg, it is not clear from the available abstract how the interactions of this pain triad were analyzed.
One would hope that survival data from at least one more phase III or phase IV clinical trial will convincingly show a prolongation of survival due to treatment with Alpharadin. This will not be inexpensive therapy. The charge to the patient for beta-emitter therapy of bone pain in one large American teaching hospital is between $8,000 and $15,000.
The authors are to be congratulated for summarizing the available data so well.
Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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